Natural Bioactive Thiazole-Based Peptides from Marine Resources: Structural and Pharmacological Aspects

marine drugs

Review Natural Bioactive Thiazole-Based Peptides from Marine Resources: Structural and Pharmacological Aspects

1, , 2, , 3 4 Rajiv Dahiya * † , Sunita Dahiya * †, Neeraj Kumar Fuloria , Suresh Kumar , Rita Mourya 5, Suresh V. Chennupati 6, Satish Jankie 1, Hemendra Gautam 7, Sunil Singh 8, Sanjay Kumar Karan 9, Sandeep Maharaj 1, Shivkanya Fuloria 3, Jyoti Shrivastava 10, Alka Agarwal 11, Shamjeet Singh 1, Awadh Kishor 12, Gunjan Jadon 13 and Ajay Sharma 14

1 School of Pharmacy, Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad & Tobago; [email protected] (S.J.); [email protected] (S.M.); [email protected] (S.S.) 2 Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico, Medical Sciences Campus, San Juan, PR 00936, USA 3 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, AIMST University, Semeling, Bedong 08100, Kedah, Malaysia; [email protected] (N.K.F.); [email protected] (S.F.) 4 Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, Haryana, India; sureshmpharma@rediffmail.com 5 School of Pharmacy, College of Medicine and Health Sciences, University of Gondar, P.O. Box 196, Gondar 6200, Ethiopia; [email protected] 6 Department of Pharmacy, College of Medical and Health Sciences, Wollega University, P.O. Box 395, Nekemte, Ethiopia; sureshchennupati@rediffmail.com 7 Arya College of Pharmacy, Dr. A.P.J. Abdul Kalam Technical University, Nawabganj, Bareilly 243407, Uttar Pardesh, India; [email protected] 8 Department of Pharmaceutical Chemistry, Ideal Institute of Pharmacy, Wada, Palghar 421303, Maharashtra, India; [email protected] 9 Department of Pharmaceutical Chemistry, Seemanta Institute of Pharmaceutical Sciences, Jharpokharia, Mayurbhanj 757086, Orissa, India; sanjay_karan21@rediffmail.com 10 Department of Pharmaceutical Chemistry, The Oxford College of Pharmacy, Hongasandra, Bangalore 560068, Karnataka, India; [email protected] 11 Department of Pharmaceutical Chemistry, U.S. Ostwal Institute of Pharmacy, Mangalwad, Chittorgarh 313603, Rajasthan, India; [email protected] 12 Department of Pharmaceutical Biotechnology, Shrinathji Institute of Pharmacy, Nathdwara 313301, Rajsamand, Rajasthan, India; [email protected] 13 Department of Pharmaceutical Chemistry, Shrinathji Institute of Pharmacy, Nathdwara 313301, Rajsamand, Rajasthan, India; [email protected] 14 Department of Pharmacognosy and Phytochemistry, School of Pharmaceutical Sciences, Delhi Pharmaceutical Sciences and Research University, New Delhi 110017, India; [email protected] * Correspondence: [email protected] (R.D.); [email protected] (S.D.); Tel.: +1-868-493-5655 (R.D.); +1-787-758-2525 (ext. 5413) (S.D.) These authors contributed equally to this work. † Received: 25 May 2020; Accepted: 19 June 2020; Published: 24 June 2020

Abstract: Peptides are distinctive biomacromolecules that demonstrate potential cytotoxicity and diversified bioactivities against a variety of microorganisms including bacteria, mycobacteria, and fungi via their unique mechanisms of action. Among broad-ranging pharmacologically active peptides, natural marine-originated thiazole-based oligopeptides possess peculiar structural features along with a wide spectrum of exceptional and potent bioproperties. Because of their complex nature and size divergence, thiazole-based peptides (TBPs) bestow a pivotal chemical platform in drug

Mar. Drugs 2020, 18, 329; doi:10.3390/md18060329 www.mdpi.com/journal/marinedrugs Mar. Drugs 2020, 18, 329 2 of 43

discovery processes to generate competent scaﬀolds for regulating allosteric binding sites and peptide–peptide interactions. The present study dissertates on the natural reservoirs and exclusive structural components of marine-originated TBPs, with a special focus on their most pertinent pharmacological proﬁles, which may impart vital resources for the development of novel peptide-based therapeutic agents.

Keywords: azole-based peptide; marine sponge; peptide synthesis; cytotoxicity; cyanobacteria; thiazole; bioactivity

1. Introduction Heterocycles are known to govern a lot of processes of vital significance inside our body, including transmission of nerve impulses, hereditary information, and metabolism. A variety of the naturally occurring congeners, including reserpine, morphine, papaverine, and quinine, are heterocycles in origin, and many of the synthetic bioactives viz. methotrexate and isoniazid contain heterocyclic pharmacophores [1]. Among heterocycles, thiazoles have received special attention as promising scaffolds in the area of medicinal chemistry because this azole has been found alone or incorporated into the diversity of therapeutic active agents such as sulfathiazole, combendazole, niridazole, fanetinol, bleomycin, and ritonavir, which are associated with antibiotic, fungicidal, schistozomicidal, anti-inflammatory, anticancer, and anti-HIV properties [2,3]. Peptides are bioactive compounds of natural origin available in all living organisms and are known for their vital contribution in a wide array of biological activity. Due to their therapeutic abilities, peptides have received growing interest in recent years. In the human body, peptides perform a lot of essential functions including the engagement of peptide hormones like insulin, glucagon-like peptide-1 (GLP-1), and glucagon and in blood glucose regulation and are used to treat novel targets for certain disease conditions, including Alzheimer’s disease, diabetes mellitus type 2, and obesity [4–7]. As unique structural features make azole-containing heterocyclic peptides (especially thiazoles) attractive lead compounds for drug development as well as nice tools for advance research, efforts should be made by scientists to develop biologically active thiazole-based peptide derivatives (TBPs). TBPs are obtained from diverse resources, primarily from cyanobacteria, sponges, and tunicates. A thiazole ring can be part of a cyclic structure or connected in a linear chain of peptides either alone or with other heterocycles like oxazole (e.g., thiopeptide antibiotics), imidazole, and indole (in the forms of histidine and tryptophan), thiazoline, oxazoline, etc. Cyclic peptides have an advantage over their linear counterparts as cyclization offers a reduction in conformational freedom, resulting in higher receptor-binding affinities. Understanding the structure–activity relationship (SAR), different modes of action, and routes of synthesis as tools are of vital significance for the study of complex molecules like heterocyclic bioactive peptides, which have a broad spectrum of pharmacological activities associated with them. Further, the sudden increase in the number of peptide drug products is another good reason to study this particular category of compounds on a priority basis. Keeping in view the vital significance of TBPs, the current article focuses on different bioactive marine-derived thiazole-based polypeptides with complex structures and their potent resources, synthetic methodologies, stereochemical aspects, structural activity relationships, diverse modes of action, and bioproperties.

1.1. Resources Various natural sources of TBPs and other heterocyclic rings containing cyclopolypeptides comprise cyanobacteria [8–40], ascidians [41–62], marine sponges [63–70], and sea slugs [71–73]. Moreover, actinomycetes, sea hare, red alga, and higher plants [74–80] were found to be other potential resources of TBPs. Mar. Drugs 2020, 18, 329 3 of 43

1.2. Linear vs. Cyclic Peptides In linear peptides with amino acid units between 10 to 20, secondary structures like α-helices and β-strands begin to form, which impose constraints that reduce the free energy of linear peptides. Compared to linear peptides, cyclopeptides are typically considered to have even greater potential as therapeutic agents due to their increased chemical and enzymatic stability, receptor selectivity, and improved pharmacodynamic properties. Although peptide cyclization generally induces structural constraints, the site of cyclization within the sequence can affect the binding affinity of cyclic peptides. Cyclization is a well-known technique to increase the potency and in vivo half-life of peptide molecules by locking their conformation. Hence, both the biological activity and the stability of peptides can be improved by cyclization. The reduction in conformational freedom brought about by cyclization often results in higher receptor-binding affinities. Overall, cyclization of peptides is a vital tool for structure–activity studies and drug development because ring formation limits the flexibility of the peptide chain and allows for the induction or stabilization of active conformations. Moreover, cyclic peptides are less sensitive to enzymatic degradation [81]. The cyclization process often increases the stability of peptides, can prolong their bioeffect, and can create peptides with the ability to penetrate tumors in order to enhance the potency of anticancer drugs [82,83]. Cyclization is envisioned to enhance the selective binding, uptake, potency, and stability of linear precursors. The prolonged activity may even be the result of additional resistance to enzymatic degradation by exoproteases. Cyclic peptides are of considerable interest as potential protein ligands and might be more cell permeable than their linear counterparts due to their reduced conformational flexibility. Further, cyclic nature of peptides was found to be crucial to their bioactivity in the case of depsipeptides. For example, corticiamide A is a member of a family of structurally related cyclic depsipeptides with tryptophan moiety that include the discodermins, halicylindramides, polydiscamide A, and microspinosamide A. However, corticiamide A is the only member of the family to contain a p-Br-Phe at residue 11 and an N-MeAsn. Microspinosamide A and polydiscamide A contained the unusual β-Me-Ile at residue 6, whereas the same amino acid is found at residue 5 in corticiamide A. All these peptides were known to be cytotoxic in the low µM range and to inhibit the growth of bacteria and fungi in addition to inhibition of the cytopathic effect of HIV-1 in mosaic human T cell leukemia cells-Syncitial Sensitive (CEM-SS) by microspinosamide A. Interestingly, the cyclic nature of these peptides was important for their bioactivity, with linear versions exhibiting a loss of activity of at least 1 order of magnitude [84,85].

2. Chemistry

2.1. Structural Features of Thiazole (Tzl)-Containing Cyclooligopeptides Aestuaramides, banyascyclamides, ulongamides (1–3), guineamides (4,5), microcyclamides MZ602 and MZ568, trichamide, tawicyclamides (6,7), obyanamide (8), cyclodidemnamide and cyclodidemnamide B, lyngbyabellins, oriamide (9), scleritodermin A (10), haligramide A (11), waiakeamide (12), haligramide B (13), mollamide C (15), jamaicensamide A (16), myotamides, didmolamides, dolastatin 3, homodolastatin 3, sanguinamides, cyclotheonellazoles, aeruginazole A, aeruginazole DA1497, aeruginazole DA1304, and aeruginazole DA1274 are examples of heterocyclic thiazole-based polypeptides having diverse unusual structural features from marine organisms. Cyanobactin cyclopolypeptide aestuaramide A contained valylthiazole (Val-Tzl) and prolylthiazole (Pro-Tzl) residues in addition to proline, valine, and methionine units and a reverse O-Tyr isoprene moiety (Ptyr). Aestuaramide B was found to be an unprenylated analogue of aestuaramide A, whereas aestuaramide C was found to be a forward C-prenylated derivative. Aestuaramide D–F and aestuaramide J–L were found to be the sulfoxide derivatives of aestuaramides A–C and aestuaramides G–I, respectively. Similarily, aestuaramides G L were reverse O-prenylated, unprenylated, or forward − C-prenylated congeners, with or without Met oxidation, but contained alanylthiazole (Ala-Tzl) instead Mar. Drugs 2020, 18, 4 of 42 Mar. Drugs 2020, 18, 329 4 of 43 Mar. Drugs 2020, 18, 4 of 42 Cyclic peptides such as aestuaramides may be exceptionally widespread metabolites in natural ecosystemsofCyclic a Val-Tzl peptides [10]. unit of such aestuaramides as aestuaramides A–F. Cyclic may peptides be exceptio suchnally as aestuaramides widespread metabolites may be exceptionally in natural widespreadecosystemsBanyascyclamides [10]. metabolites B in and natural C are ecosystems modified [10 cyclopolypeptides,]. closely related in structure, and composedBanyascyclamides of two thiazole B B - andalanine and C C are units. are modified modified The cyclohexapeptide cyclopolypeptides, cyclopolypeptides, banyascyclamide closely closely related related C in exhibited structure in structure, close, and structuralandcomposed composed siofmilarity twoof twothiazole with thiazole-alanine - banyascyclamidealanine units. units. The A cyclohexapeptide The but cyclohexapeptide differed in havingbanyascyclamide banyascyclamide L-phenylalanyl C exhibited- CL-threonine exhibited close moiety instead of L-Phe-mOzl residue of banyascyclamide A. Similarily, banyascyclamide B differed closestructural structural similarity similarity with with banyascyclamide banyascyclamide A but A but differed differed in in having having Ll--phenylalanyl-phenylalanyl-Ll-threonine-threonine from banyascyclamide C in having L-leucyl-L-threonine moiety instead of moiety instead of lL-Phe-mOzl-Phe-mOzl residue of banyascyclamide A. Similarily, banyascyclamide B differed differed L-phenylalanyl-L-threonine residue [11]. from banyascyclamide banyascyclamide C in having C l in-leucyl- havingl-threonine L-leucyl moiety-L-threonine instead of l-phenylalanyl moiety instead-l-threonine of The cyanobacterium-derived ulongamide A (1) and other ulongamides B–F are alanine-derived residueL-phenylalanyl [11]. -L-threonine residue [11]. thiazoleThe carboxylic cyanobacterium-derivedcyanobacterium acid - (derivedL-Ala-Tzl ulongamide-ca) containing A (1) andcyclodepsipeptides other ulongamides which B–FB–F possessedare alanine-derivedalanine - aderived novel β-amino acid residue, 3-amino-2-methylhexanoic acid (Amha). Further, there was the presence of thiazole carboxylic acid ( (lL-Ala-Tzl-ca)-Ala-Tzl-ca) containing cyclodepsipeptides which possessed a novel 2-hydroxyisovaleric acid (Hiva) in ulongamide D (2) and 2-hydroxy-3-methylpentanoic acid (Hmpa) β--aminoamino acid residue, residue, 3 3-amino-2-methylhexanoic-amino-2-methylhexanoic acid acid (Amha). (Amha). Further, Further, there there was was the the presence presence of in ulongamide E and ulongamide F (3), which had replaced the L-lactic acid moiety present in of2-hydroxyisovaleric 2-hydroxyisovaleric acid acid (Hiva) (Hiva) in ulongamide in ulongamide D (2) and D ( 22)-hydroxy and 2-hydroxy-3-methylpentanoic-3-methylpentanoic acid (Hmpa) acid ulongamides A–C. Ulongamides A–E displayed weak in vitro cytotoxicity against ubiquitous (Hmpa)in ulongamide in ulongamide E and ulongamide E and ulongamide F (3), Fwhich (3), which had replaced had replaced the L the-lacticl-lactic acid acid moiety moiety present present in KERATIN-forming tumor cell subline (KB) and LoVo cells [13] (Figure 1). inulongam ulongamidesides A– A–C.C. Ulongamides Ulongamides A– A–EE displayed displayed weak weak inin vitro vitro cytotoxicity against ubiquitousubiquitous KERATIN-formingKERATIN-forming tumortumor cellcell sublinesubline (KB)(KB) andand LoVoLoVo cellscells [13[13]] (Figure (Figure1 ).1).

S S HN HN HN N N S N S S HN N O HN HN N O O O N N O O N N S O HN HN O O O HN N O O O N N O O O O O NH O O O HN HN O O HN N O N O O O O O O O NH O O N N O HO O O HO 1 2 3 Figure 1. Structures1 of ulongamide A (1), ulongamide2 D (2), and ulongamide F (33) with alanyltFigurehiazole 1. 1.Structures Structures (Ala-Tzl of ) ulongamide ofand u longamide3-amino A-2 (1- methylhexanoic),A ulongamide (1), ulongamide D acid (2), and( Amha D ulongamide(2), moietand iesu Flongamide. (3) with alanylthiazole F (3) with (Ala-Tzl)alanylthiazole and 3-amino-2-methylhexanoic (Ala-Tzl) and 3-amino-2-methylhexanoic acid (Amha) moieties. acid (Amha) moieties. The cyanobacterium-derived guineamide A (4) contained the common L-alanine-disubstituted- thiazoleThe unit, cyanobacterium-derivedcyanobacterium unique β-amino-derived acid guineamide 2-methyl -A 3- aminopentanoic( 4) contained the acidcommon (Mapa), Ll--alanine-disubstituted-alanine lactic- disubstituted acid (L-Lac),- L Nthiazole-methylated unit, unique amino β acids--aminoamino viz. acid N 2-methyl-3-aminopentanoic2--methylphenylalaninemethyl-3-aminopentanoic ( -N - acidMePhe), (Mapa), and lactic lactic N- methylvaline acid (Ll--Lac),Lac), L (N--methylated-Nmethylated-MeVal), but amino amino guineamide acids acids viz. BNviz. -methylphenylalanine(5) deviatedN-methylphenylalanine from guineamide (l-N-MePhe), (AL- N(4- and)MePhe), in Nhaving-methylvaline and 2-hydroxyisovaleric N-methylvaline (l-N-MeVal), L L acidbut(L-N guineamide(-MeVal),-Hiv) and but 2 B -guineamidemethyl (5) deviated-3-aminobutanoic B from(5) deviated guineamide acid from (Maba) Aguineamide (4) inunits having instead A ( 2-hydroxyisovaleric4) inof having-Lac an 2d-hydroxyisovaleric Mapa acid units. (l-Hiv) The absoluteandacid 2-methyl-3-aminobutanoic(L-Hiv) stereochemistry and 2-methyl of-3 -theaminobutanoic 2 acid-methyl (Maba)-3- aminopentanoicacid units (Maba) instead units of acid linstead-Lac (Mapa) and of MapaLunit-Lac inan units. dguineamide Mapa The units. absolute A The(4) wasstereochemistryabsolute found stereochemistry to be of the 2S,3 2-methyl-3-aminopentanoicR. of From the 2 a- methyl biosynthetic-3-aminopentanoic perspective, acid (Mapa) acid the unit (Mapa) guineamides in guineamide unit in were Aguineamide (4 ) found was found toA be( to4) interestingbewas 2S found,3R. From molecules to abe biosynthetic 2S ,3 becauseR. From perspective, of a the biosynthetic presence the guineamides of perspective, unusual  were- amino the found guineamides and to β- behydroxy interesting were acid found molecules residues. to be Further,becauseinteresting guineamide of the molecules presence B because(5 of) exhibited unusual of theα moderate-amino presence and cytotoxic ofβ -hydroxy unusu activityal acid-amino against residues. and a mouse βFurther,-hydroxy neuroblastoma guineamide acid residues. Bcell (5) lineexhibitedFurther, [14] (Figureguineamide moderate 2). cytotoxic B (5) exhibited activity moderate against a cytotoxic mouse neuroblastoma activity against cell a linemouse [14 ]neuroblastoma (Figure2). cell line [14] (Figure 2). O S S O O N S N N O H N S H NH N N N O N O H O H N O HN O NH O O O N N O O N HN N O O N O N N O O O O O O O 4 5

FigureFigure 2. Structures ofof guineamide guineamide4 A A (4 )(4 and) and guineamide guineamide B (5 ) B with (5) with Ala-Tzl Ala5 and-Tzll -andN-Methylated L-N-Methy aminolated aminoacid units. acid units. Figure 2. Structures of guineamide A (4) and guineamide B (5) with Ala-Tzl and L-N-Methylated amino acid units.

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Microcyclamides MZ602 and MZ568 contained isoleucylthiazole moiety in common but differedMicrocyclamides in having phenylalanine MZ602 and and MZ568 glycine contained amino isoleucylthiazoleacids in the former moiety and valine in common and alanine but di inffered the latter.in having Trichamide phenylalanine possessed and serylthiazole glycine amino and acids leucylthiazole in the former moieties and valine in addition and alanine to histidine in the amino latter. acidTrichamide [18]. possessed serylthiazole and leucylthiazole moieties in addition to histidine amino acid [18]. The cyanobacterium-derived cyanobacterium-derived lyngbyabellin lyngbyabellin A is A a significantly is a significantly cytotoxic cytotoxic dichlorinated dichlorinated peptolide peptolidewith unusual with structural unusual features, structural including features, a dichlorinated including a dichlorinatedα-hydroxy acid -hydroxy and two functionalized acid and two functionalizedthiazole carboxylic thiazole acid carboxylic units. This acid depsipeptide units. This wasdepsipeptide found to bewas a potentfound to disrupter be a potent of the disrupter cellular ofmicrofilament the cellular networkmicrofilament [27]. Lyngbyabellin network [27]. BLyngbyabellin is related cyclic B depsipeptideis related cyclic in whichdepsipeptide one thiazole in which unit onewas replacedthiazole unitby a thiazolinewas replaced ring, by with a thiazoline the placement ring, of with the ringthe placemen between thet of glycine the ring residue between and the glycineα,β-dihydroxyisovaleric residue and the  acid,β-dihydroxyisovaleric rather than adjacent acid to the rather valine-derived than adjacent unit, to and the the valine isoleucine-derived-derived unit, andunit inthe lyngbyabellin isoleucine-derived A was unit replaced in lyngbyabellin by a valine-derived A was moiety replaced in lyngbyabellin by a valine-derived B. Lyngbyabellin moiety in lyngbyabellinB displayed potent B. Lyngbyabellin toxicity toward B displayed brine shrimp potent and toxicity the fungus towardCandida brine albicans shrimpand and was the found fungus to Candidabe slightly albicans less cytotoxicand was foundin vitro tothan be slightly lyngbyabellin less cytotoxic A against in vitro KB andthan LoVolyngbyabellin cells, respectively A against [ 86KB]. andThe structuresLoVo cells, of respectively lyngbyabellin [86 E]. andThe Hstructures showed theof lyngbyabellin presence of two E and 2,4-disubstituted H showed the thiazole presence rings of twoand 2,4 diff-disubstitutedered7 in having thiazole the α rings,β-dihydroxyisovaleric and differed7 in having acid (dhiv) the ,β unit-dihydroxyisovaleric in lyngbyabellin acid E replaced (dhiv) unitby the in 2-hydroxyisovaleric lyngbyabellin E replaced acid (hiva) by the unit 2- inhydroxyisovaleric lyngbyabellin H. acid Intriguingly, (hiva) unit lyngbyabellin in lyngbyabellin E and H. H Intriguingly,appeared to be lyngbyabellin more active againstE and H the appeared H460 human to be lungmoretumor active cellagainst lines. the From H460 the human bioactivity lung results,tumor cellit appeared lines. From that the lung bioact tumorivity cell results, toxicity it is appeared enhanced that in the lung cyclic tumor representatives cell toxicity withis enhanced an elaborated in the cyclicside chain representatives [28]. with an elaborated side chain [28]. In addition to two thiazole rings and a chlorinated 2 2-methyloctanoate-methyloctanoate residue, lyngbyabellin N contained an an unusual unusual dimethylated dimethylated valine valine terminus terminus and a and leucine a leucine statine statineresidue. residue. The planar The structure planar structureof lyngbyabellin of lyngbyabellin N was closely N relatedwas closely to that related of lyngbyabellin to that of H lyngbyabellin except for the replacement H except for of the replacementpolyketide portion of the with polyketide an N,N -dimethylvaline portion with an (DiMeVal) N,N-dimethylvaline residue [29]. (DiMeVal) The cytotoxic residue lyngbyabellin [29]. The J cytotocontainedxic the lyngbyabellingem-dichloro moiety J contained as part of the a 7,7- gem dichloro-3-acyloxy-2-methyloctanoate-dichloro moiety as part of residue a 7,7 in- dichloroaddition-3 to-acyloxy the α,β--dihydroxy-2-methyloctanoateβ-methylpentanoic residue in addition acid (Dhmpa, to the C,β19–24-dihydroxy) unit and-β two-methylpentanoic disubstituted acidthiazole (Dhmpa, rings C [3019–].24) unit and two disubstituted thiazole rings [30]. Tawicyclamides A A and an Bd (6 B,7 )( represent6,7) represent a novel a category novel category of cyclooligopeptides, of cyclooligopeptides,bearing alternative bearing alternativesequences sequence of twos thiazoles of two thiazoles and one and thiazoline one thiazoline amino amino acid acid but but lacking lacking the the oxazolineoxazoline ring ring,, which is characteristic of ascidian-derivedascidian-derived heptapeptides lissoclinamides and the octapeptidesoctapeptides patellamides/ulithiacyclamides.patellamides/ulithiacyclamides. Moreover, the presence of a cis--valine-prolinevaline-proline amide bond facilitates an unusual threethree-dimensional-dimensional conformation conformation to to ascidian ascidian-derived-derived tawicyclamides tawicyclamides A A and and B B ( (66,,77)).. Tawicyclamide B (7) didiffersffers from tawicyclamide A (6) inin having a leucine moiety in place of the phenylalanine residue of tawicyclamide A [[41]41] (Figure(Figure3 3).).

O O N H N H N N

O NH O NH O S O S N N

N N S S H NH O H NH O N N N N

O S O S

6 7

Figure 3. Structures of t tawicyclamideawicyclamide A ( 6)) and t tawicyclamideawicyclamide B B ( (7)) with valylthiazole ( (Val-Tzl)Val-Tzl) and Ll--isoleucyl-thiazoleisoleucyl-thiazole ( (Ile-Tzl)Ile-Tzl) moieties.moieties.

In the structurestructure of of depsipeptide–obyanamidedepsipeptide–obyanamide ((8),), the alanylthiazole (Ala(Ala-Tzl)-Tzl) unit and 33-aminopentanoic-aminopentanoic acid acid (Apa) were present [12,42][12,42] whereas the sponge-derivedsponge-derived cytotoxic cyclic peptide, oriamide ( 9)),, was found to contain a new 4-propenoyl-2-tyrosylthiazole4-propenoyl-2-tyrosylthiazole ami aminono acid acid (PTT) (PTT) moiety. Further, Further, a novel conjugated conjugated thiazole thiazole moiety moiety viz.viz. 2-(1-amino-2-2-(1-amino-2-p--hydroxyphenylethane)-4-hydroxyphenylethane)-4-

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(4-carboxy-2,4-di-methyl-2(4(4--carboxy--2,4--di--methyl--2ZZ,4,4,4EE---propadiene)-thiazolepropadiene)--thiazolethiazole (ACT)(ACT) (ACT) waswas was foundfound found toto to bebe be partpart part ofof of thethe the structurestructure structure ofof oftubulintubulin tubulin inhibitory inhibitory inhibitory sponge sponge sponge-derived--derived cyclopolypept cyclopolypeptideideide s scleritodermin scleritodermin A A ((10 (10)),),, along along along with with OO-methyl---methyl--NN-sulfoserine--sulfoserine andand keto-keto--alloallo-isoleucine--isoleucineisoleucine unitsunitsunits [[64][64]64] (Figure(Figure(Figure4 4).))..

OH OH

OH OH H H O N O N HO H O HO O N H O O N N H N H N H N O O N H O O N N N H N O N NH H O HN NH S O O HN O NH S O O NH O O H NH O NH O H H O S O O H O S O O O N O NaO3S O N NaO3S N N O O N N O NH O NH O NH NH S NH O NH O O S N O O N N N O N O N O O O O O O NHSO Na NHSO3 Na OH 3 OH 8 9 10

FigureFigure 4. 4. StructuresStructures of ofobyanamide obyanamide ((8 ())8 )with with Ala Ala-Tzl--Tzl moiety, moiety, o oriamideriamideriamide (( 99)) withwith 4-propenoyl-2-tyrosylthiazole4--propenoyl--2--tyrosylthiazoletyrosylthiazole amino amino acid acid ((PTT) (PTT)) moiety moiety,,, and s scleritoderminscleritodermincleritodermin A A (10)) withwith 2-(1-amino-2-2--(1(1--amino--2--p--hydroxyphenylethane)-4--hydroxyphenylethane)--4-- (4-carboxy-2,4-di-methyl-2(4(4--carboxycarboxy--2,4--di--methyl--2ZZ,4,4,4EE-propadiene)-thiazole--propadiene)--thiazolethiazole (ACT)((ACT)) moiety.moiety..

InIn thethe the structurestructure structure ofof of thethe the bisthiazolebisthiazole bisthiazole-containing--containing macrocyclic macrocyclic peptide peptide,,, cyclodidemnamide cyclodidemnamide B, two B, l d twothiazolethiazole thiazole moietiesmoieties viz. viz.prolylthi prolylthiazoleazole (L--Pro (--Tzl)-Pro-Tzl) and leucylthiazole and leucylthiazole (D--Leu (--Tzl)-Leu-Tzl) were found werefound found toto be topresent be present... The ascidian The ascidian-derived--derived cyclodidemnamide cyclodidemnamide was was found found to to be be similar similar to to reverse reverse prenyl prenyl substitutedsubstituted cytotoxic cytotoxic cycloheptapeptide cycloheptapeptide mollamide mollamide only in possessing only the in same possessing dihyrothiazole-proline the same 20 27 dipeptidedihyrothiazole unit--proline (C20–C27 ),dipeptide but it also unit contained (C 20–C leucylthiazole27),), but but it it also also and phenylalanyl-methyl contained contained leucylthiazole leucylthiazole oxazoline and and moietiesphenylalanyl [43,62--methyl]. oxazoline moieties [43,62]. TheThe sponge-derivedsponge--derived cytotoxic cytotoxic hexapeptides hexapeptides haligramide haligramide A A and and B (B11 ((,1113,,)13 were)) were found foundfound to contain toto containcontain the phenylalanylthiazolethethe phenylalanylphenylalanylthiazolethiazole (Phe-Tzl) (Phe(Phe--Tzl) moiety moiety in addition inin addiadditiontion to three toto threethree proline prolineproline units. units.units. Haligramide Haligramide A (11 A) (( was11)) wa thes bismethioninethethe bismethionine bismethionine analogue analogue analogue of waiakeamide of of waiakeamide (12), bearing ((12)),, bearing bearing Phe-Tzl Phe moiety.--Tzl Haligramide moiety.. Haligramide Haligramide B (13) contained B B ((13)) bothcontained methionine both methionine and methionine and methionine sulfoxide sulfoxide residues residues in comparison in comparison to haligramide to haligramide A (11) whichA ((11)) containedwhich contain only methionineed only methionine residues and residues waiakeamide and (w12aiakeamide), another sponge-derived ((12)),, another another cyclohexapeptide sponge sponge--derived thatcyclohexapeptide contained methionine thatthat containcontain sulfoxideed methionine residues sulfoxide only [63,66 residues] (Figure only5). [[63,,66]] (Figure(Figure 5))..

S S O O O H O H O H H O O N N NH O N S N NH S N O N O N S N N O N S N O N N N O S O N S N O O NH O O O NH N O N NH NH NH S O O NH NH NH S O O O NH O NH O N N S O N N NH S NH N N N O O N N N S O O S O S S O O S O O O S O O O O

11 12 13

FigureFigure 5. 5. StructuresStructures of of h haligramidealigramide A A (( 1111))),,, w waiakeamideaiakeamide (( (1212))),,, and and h haligramidealigramide B B ( (13)) withwith phenylalanylthiazolephenylalanylthiazole (Phe-Tzl)(Phe--Tzl)) moieties.moietiesies..

A unique amino acid,, 2--bromo--5--hydroxytryptophan (BhTrp),, and an unusual ureido linkage were found to be present in the composition of sponge--derived peptide konbamide with calmodulin

Mar. Drugs 2020, 18, 329 7 of 43

Mar. DrugsA unique 2020, 18 amino, acid, 2-bromo-5-hydroxytryptophan (BhTrp), and an unusual ureido linkage7 of 42 were found to be present in the composition of sponge-derived peptide konbamide with calmodulin antagonisticantagonistic activity activity [[8787].]. F Further,urther, the cytotoxiccytotoxic depsipeptide depsipeptide polydiscamide A contained contained aa novel novel aminoamino acidacid 3-methylisoleucine3-methylisoleucine inin additionaddition toto heterocyclicheterocyclic tryptophantryptophan moietymoiety [[6565,8,888].]. TheThe notaspidean mollusk mollusk-derived-derived cytotoxic cytotoxic cyclic cyclic hexapeptide hexapeptide k keenamideeenamide A A (14 (14) )contain containeded a aleuylthiazol leuylthiazolineine (L (Leu-Tzn)eu-Tzn) unit unit together together with with serylisoprene serylisoprene residue residue in its in structure its structure and differ and diedﬀ fromered frommollamide mollamide C (15 C), ( a15 tunicate), a tunicate-derived-derived cyclo cyclohexapeptide,hexapeptide, in having in having thiazoline thiazoline moiety moiety instead instead of ofthiazole thiazole [72 []72. Trunkamide]. Trunkamide A contain A containeded a thiazoline a thiazoline heterocycle heterocycle and andtwo tworesidues residues of Ser of and Ser Thr and with Thr withthe hydroxy the hydroxy function function modified modiﬁed as reverse as reverse prenyl prenyl (rPr). (rPr). The The structure structure of ofjamaicensamide jamaicensamide A A(16 (16), ),a asponge sponge-derived-derived peptidepeptide having having ββ-amino-amino--αα-keto-keto and and thiazole thiazole-homologated-homologated ηη--aminoamino acid residues, waswas found found to to contain contain 2-aminobutanoic2-aminobutanoic acid acid (Aba), (Aba), 5-hydroxytryptophan 5-hydroxytryptophan (HTrp),(HTrp), andand a a terminal terminal 2-hydroxy-3-methylpentanamide2-hydroxy-3-methylpentanamide (Hmp)(Hmp) unitunit [[4444,,8899]] (Figure(Figure6 ).6).

O H NH N NH H O O O NH N N NH NH NH O O O NH O O S O O O NH N O O O N HN O O S O N N O N N NH S H N O H 14 15 16

FigureFigure 6.6. Structures of keenamidekeenamide A (14) with leuylthiazolineleuylthiazoline (Leu-Tzn)(Leu-Tzn) moiety moiety,, mollamidemollamide C (15) withwith Leu-TzlLeu-Tzl moiety,moiety, andand jamaicensamidejamaicensamide AA ((1616)) withwith Ala-TzlAla-Tzl andand 2-hydroxy-3-methylpentanamide2-hydroxy-3-methylpentanamide (Hmp)(Hmp) residues.residues.

MyotamidesMyotamides A andand B B are are ascidian-derived ascidian-derived cycloheptapeptides cycloheptapeptides that that contained contained threethree unusual unusual aminoamino acidsacids containingcontaining heteroatomsheteroatoms including one thiazole (Tzl) and twotwo thiazolinethiazoline (Tzn)(Tzn) ringsrings inin additionaddition to to valine, valine, proline, proline, isoleucine, isoleucine and, methionine. and methionine. Mayotamide Mayotamide A embodied A embodiedthe same Val-Pro-Tzn the same sequenceVal-Pro-Tzn as was sequence found as in was ascidian-derived found in ascidian cyclic-derived heptapeptide cyclic cyclodidenmamideheptapeptide cyclodidenmamide and also contained and analso additional contained thiazoline an additional (Tzn) thiazolinering. Myotamide (Tzn) ring. A di ffMyotamideered from myotamideA differed B from in having myotamide isoleucine B in moiety,having whichisoleucine was replacedmoiety, which by valine was moiety replaced in the by latter.valine Both moiety cyclopolypeptides in the latter. Both exhibited cyclopolypeptides cytotoxicity againstexhibited tumor cytotoxicity cell lines against [45]. tumor cell lines [45]. DidmolamideDidmolamide BB isis aa thiazole-containingthiazole-containing ascidian-derivedascidian-derived cyclopolypeptidecyclopolypeptide thatthat containedcontained twotwo lL-alanylthiazole-alanylthiazole residues,residues, andand lL-phenylalanine-phenylalanine andand lL-threonine-threonine moieties.moieties. The threoninethreonine residueresidue ofof didmolamidedidmolamide BB waswas modifiedmodified to to a a methyloxazoline methyloxazoline (mOzn) (mOzn) heterocycle heterocycle in in the the case case of of didmolamide didmolamide A. DidmolamideA. Didmolamide B was B was found found to exhibit to exhibit mild mild cytotoxicity cytotoxicity against against several several cultured cultured tumor tumor cell lines cell [lines48]. [48]. Dolastatin 3 is a cyanobacterium- as well as sea hare-derived cyclopolypeptide that contained two lDolastatin-glutaminyl-thiazole 3 is a cyanobacterium (l-Gln-Tzl)- andas well glycyl-thiazole as sea hare-derived (Gly-Tzl) cyclopolypeptide units in addition that to containedl-valine, ltwo-leucine, L-glutaminyl and l-proline-thiazole residues. (L-Gln-Tzl) The and cyanobacterium-derived glycyl-thiazole (Gly-Tzl) homodolastatin units in addition 3 di ff toered L-valine, from dolastatinL-leucine, and 3 by L the-proline addition residues of a. methyleneThe cyanobacterium group, i.e.,-derived an l-isoleucine homodolastatin residue 3 in differ placeed of from the ldolastatin-valine residue 3 by the of addition dolastatin of a 3. methylene The cyclopentapeptide group, i.e., an L dolastatin-isoleucine 3residue was found in place to of exhibit the L- HIV-1valine integraseresidue of inhibitory dolastatin activity 3. The as cyclopentapeptide well as P388 lymphocytic dolastatin leukemia 3 was (PS) found cell to growth exhibit inhibitory HIV-1 integrase activity. Kororamideinhibitory activity is another as cyanobacterium-derived well as P388 lymphocytic polypeptide leukemia having (PS) two celll -tyrosinyl-thiazole growth inhibitory (l -Tyr-Tzl) activity. andKororamide leucyl-thiazoline is another (Leu-Tzn) cyanobacterium units in addition-derived to polypeptidel-leucine, l-isoleucine, having twol-serine, L-tyrosinyll-proline,-thiazole and l(L-asparagine-Tyr-Tzl) and residues leucyl [9-thiazol,90]. ine (Leu-Tzn) units in addition to L-leucine, L-isoleucine, L-serine, L-proline, and L-asparagine residues [9,90]. The sponge-derived cyclotheonellazoles A–C are unusual cyclopolypeptides containing nonproteinogenic acids, the most unique being 4-propenoyl-2-tyrosylthiazole (PTT), 3-amino-4-methyl-2-oxohexanoic acid (Amoha), and diaminopropionic acid (Dpr), along with two

Mar. Drugs 2020, 18, 329 8 of 43

The sponge-derived cyclotheonellazoles A–C are unusual cyclopolypeptides containing nonproteinogenic acids, the most unique being 4-propenoyl-2-tyrosylthiazole (PTT), 3-amino-4-methyl-2-oxohexanoic acid (Amoha), and diaminopropionic acid (Dpr), along with two or three proteinogenic amino acids like glycine and alanine. Cyclotheonellazoles B and C shared the same basic structure with cyclotheonellazole A, in which leucine (in cyclotheonellazole B) and homoalanine (in cyclotheonellazole C) replaced the 2-aminopentanoic acid residue of cyclotheonellazole A. Cyclotheonellazoles were found to be nanomolar inhibitors of chymotrypsin and sub-nanomolar inhibitors of elastase [68]. The nudibranch-derived sanguinamide A is a modified heptapeptide containing a 2-substituted thiazole-4-carboxamide moiety. Structural analysis of this peptide indicated the presence of two residues, l-proline and l-isoleucine, present in alternative continuous sequences in addition to amino acid moieties phenylalanine and alanine with an l-configuration. In this cycloheptapeptide, azole-modified amino acid was found to be l-isoleucyl-thiazole (l-Ile-Tzl). In comparison to sanguinamide A, the cyclic octapeptide sanguinamide B was found to contain additional heteroaromatic oxazole and thiazole rings [73]. The cyanobacterium-derived polythiazole peptide aeruginazole DA1497 contained leuylthiazole (Leu-Tzl), alanylthiazole (Ala-Tzl), phenylalanylthiazole (Phe-Tzl), and valylthiazole (Val-Tzl) residues and exhibited bioproperties against Gram-positive bacterium Staphylococcus aureus. However, in related cyclopolypeptides, aeruginazole DA1304 and aeruginazole DA1274 moieties like asparaginylthiazole (Asn-Tzl), Leu-Tzl and isoleucylthiazole (Ile-Tzl) were found to be present. l-Asn-Tzl moiety was also observed in the polythiazole containing cyanobacterium-derived polypeptide aeruginazole A in addition to d-Leu-Tzl and l-Val-Tzl residues. This cyclododecapeptide was found to potently inhibit the Gram-positive bacterium Bacillus subtilis [8,91].

2.2. Structural Features of Tzl-Containing Linear Peptides In addition to cyclopolypeptides, heterocyclic thiazole ring-based linear peptides are also obtained from marine organisms. Micromide (17), apramides (18,19), dolastatin 10 (20), symplostatin 1 (21), dolastatin 18 (22), lyngbyapeptins A and C (23,24), and lyngbyabellin F (25) and I (26) are the best examples of linear peptides containing thiazole rings. Micromide (17) is a highly N-methylated linear peptide containing structural features common to many cyanobacterial metabolites, including a d-amino acid, a modified cysteine unit in the form of a thiazole ring and N-methylated amino acids. The structrural components of this peptide included moieties like 3-methoxyhexanoic acid, N-Me-Gly-thiazole, and other N-methylated amino acids viz. N-Me-Phe, N-Me-Ile, N-Me-Val, etc. Micromide (17) was found to exhibit cytotoxicity against KB cells [92]. On the other hand, the cyanobacterium-derived apramides A–G are linear lipopeptides containing a thiazole-containing modified amino acid unit. Structural analysis of apramide A (18) suggested the presence of a 2-methyl-7-octynoic acid moiety (Moya) and six amino acid residues (N-Me-Ala, Pro, N,O-diMe-Tyr, and 3 units of N-Me-Val) and a C-terminally modified amino acid unit (N-Me-Gly-thz). Structures of apramide B and apramide C (19) differed from apramide A (18) in having the presence of a 7-octynoic acid unit (Oya) and 2-methyl-7-octenoic acid moiety (Moea) in lieu of the Moya moiety of apramide A (18). Apramides D–F differed from apramide A (18), B, and C (19), only by bearing a Pro-Tzl unit instead of the N-Me-Gly-Tzl residue, which had caused a drastic impact on the conformational behavior. The lipopeptide apramide A (18) was found to enhance elastase activity [93] (Figure7). Mar. Drugs 2020, 18, 8 of 42 or three proteinogenic amino acids like glycine and alanine. Cyclotheonellazoles B and C shared the same basic structure with cyclotheonellazole A, in which leucine (in cyclotheonellazole B) and homoalanine (in cyclotheonellazole C) replaced the 2-aminopentanoic acid residue of cyclotheonellazole A. Cyclotheonellazoles were found to be nanomolar inhibitors of chymotrypsin and sub-nanomolar inhibitors of elastase [68]. The nudibranch-derived sanguinamide A is a modified heptapeptide containing a 2-substituted thiazole-4-carboxamide moiety. Structural analysis of this peptide indicated the presence of two residues, L-proline and L-isoleucine, present in alternative continuous sequences in addition to amino acid moieties phenylalanine and alanine with an L-configuration. In this cycloheptapeptide, azole-modified amino acid was found to be L-isoleucyl-thiazole (L-Ile-Tzl). In comparison to sanguinamide A, the cyclic octapeptide sanguinamide B was found to contain additional heteroaromatic oxazole and thiazole rings [73]. The cyanobacterium-derived polythiazole peptide aeruginazole DA1497 contained leuylthiazole (Leu-Tzl), alanylthiazole (Ala-Tzl), phenylalanylthiazole (Phe-Tzl), and valylthiazole (Val-Tzl) residues and exhibited bioproperties against Gram-positive bacterium Staphylococcus aureus. However, in related cyclopolypeptides, aeruginazole DA1304 and aeruginazole DA1274 moieties like asparaginylthiazole (Asn-Tzl), Leu-Tzl and isoleucylthiazole (Ile-Tzl) were found to be present. L-Asn-Tzl moiety was also observed in the polythiazole containing cyanobacterium-derived polypeptide aeruginazole A in addition to D-Leu-Tzl and L-Val-Tzl residues. This cyclododecapeptide was found to potently inhibit the Gram-positive bacterium Bacillus subtilis [8,91].

O O O H H N N N N N N N

S O O O OMe Ph Ph Mar. Drugs 2020, 18, 9 of 42 17

O O O

N N N N N N N N O O O O S

O 18

O O O

N N N N N N N N O O O O S

O 19

FigureFigure 7. 7. StructuresStructures of of m micromideicromide ( 17)),, a apramidepramide A (18),), and apramideapramide C ((1919)) withwith terminalterminal NN-Me-Gly-Tzl-Me-Gly-Tzl residues.residues.

TheThe dolastatins dolastatins are are sea sea hare- hare- andand marine marine cyanobacterium-derived cyanobacterium-derived compoundscompounds thatthat exhibit exhibit cytotoxiccytotoxic properties.properties. Dolastatin 10 (20)) isis aa linearlinear thiazole-containingthiazole-containing heterocyclicheterocyclic peptidepeptide bearingbearing NN,,NN-dimethylvaline,-dimethylvaline, (3R,4,4S,5S)-dolaisoleucine,)-dolaisoleucine, (2R,3,3R,4,4S))-dolaproine,-dolaproine, and (S))-dolaphenine-dolaphenine [94].]. LikeLike dolastatin dolastatin10 10 (20 (),20 cyanobacterium-derived), cyanobacterium-derived symplostatin symplostatin 1 (21 ) 1 is ( a21 potent) is a microtubule potent microtubule inhibitor. Symplostatininhibitor. Symplostatin 1 (21) diff ered1 (21 from) differed dolastatin from dolastatin 10 (20) by 10 the (20 replacement) by the replacement of the iso-propyl of the iso group-propyl by agroupsec-butyl by groupa sec-butyl on the group first N on-dimethylated the first N-dime aminothylated acid. Symplostatin amino acid. 1 Symplostatin (21) is a very potent1 (21) cytotoxinis a very butpotent not cytotoxinas potent as but dolastatin not as potent 10 (20 ), as whereas dolastatin synthetic 10 (20) analogues, whereas lacking synthetic the analoguesN,N-dimethylamino lacking the acidN,N- residuedimethylamino were reported acid residueto be markedly were reported less cytotoxic. to be The markedly structure less of cytotoxic.symplostatin The 1 ( structure21) differed of 20 N fromsymplostatin dolastatin 1 10(21 () differed) by only from one additional dolastatin CH 10 2(20unit) by in only the one-terminal additional residue. CH2 The unit absolute in the configurationN-terminal residue. of the The stereocenter absolute atconfiguration C-26 in symplostatin of the stereocenter 1 (21) was at foundC-26 in to symplostatin be 26S. The biological1 (21) was evaluationfound to be of symplostatin26S. The biological 1 (21) revealed evaluation that of it issymplostatin highly active 1 against (21) revealed certain tumorsthat it andis highly comparable active inagainst its activity certain with tumors isodolastatin and comparable H. Both dolastainin its activity 10 ( 20with) as isodolastatin well as its methyl H. Both analog, dolastain symplostatin 10 (20) as 1 (well21) were as its found methyl to beanalog, potent symplostatin microtubule 1 depolymerizers(21) were found [95 to, 96be]. potent microtubule depolymerizers [95,9Dolastatin6]. 18 (22) is another cancer cell growth inhibitory linear peptide bearing thiazole moiety fromDolastatin the sea hare, 18 the(22) structureis another of cancer which iscell derived growth from inhibitory two α -amino linear peptide acids (Leu bearing and MePhe), thiazole amoiety dolaphenine from the(Doe) sea unit, hare, and the the structure new carboxylic of which acid is 2,2-dimethyl-3-oxohexanoic derived from two -amino acid acids (dolahexanoic (Leu and acid,MePhe), Dhex). a dolaphenine Dolastatin 18 (Doe) (22) was unit, found and to the significantly new carboxylic inhibit acid growth 2,2- ofdimethyl human- cancer3-oxohexanoic cell lines acid[97] (Figure(dolahexanoic8). acid, Dhex). Dolastatin 18 (22) was found to significantly inhibit growth of human cancer cell lines [97] (Figure 8).

Mar. DrugsMa2020r. Drugs, 18 2020, 329, 18, 10 of 42 10 of 43

Mar. Drugs 2020, 18, S 10 of 42 O N H N H N N O O N O O N O S O N H N H N N 20O O N O O N O N H S O H N H H N N O O N N N O O 20 N N O O O O O S N N H S O H N H H N N O O N N N O O N N 21 22 O O O O O S N Figure 8.FigureStructures 8. Structures of dolastatin of dolastatin 10 10 (20 (20),), symplostatin symplostatin 1 1(21 (21), ),and and dolastatin dolastatin 18 (22 18) with (22) terminal with terminal

Phe-TzlPhe residues.-Tzl residues. 21 22 Lyngbyapeptins are thiazole-containing lipopeptides with a rare 3-methoxy-2-butenoyl moiety LyngbyapeptinsFigure 8. Structures are thiazole-containing of dolastatin 10 (20), symplostatin lipopeptides 1 (21) with, and d aolastatin rare 3-methoxy-2-butenoyl 18 (22) with terminal moiety with a high level of N-methylation. The cyanobacterium-derived lyngbyapeptin A (23) is a linear Phe-Tzl residues. with amodified high level peptide of Nwith-methylation. a 2-substituted The thiazole cyanobacterium-derived ring. In comparison to lyngbyapeptin lyngbyapeptin A A(23 ()23, ) is a linear modified peptide with a 2-substituted thiazole ring. In comparison to lyngbyapeptin lyngbyapeptinLyngbyapeptins B and areC possess thiazole th-containinge same/similar lipopeptides characteristic with Ca -rare and 3 N-methoxy-terminal-2 -modificationbutenoyl moiety and A(23),withdiffer lyngbyapeptin aed high by containinglevel of BN -methylation.other and amino C possess acidThe cyanobacteriumunits the in samebetween./similar-derived Structural l characteristicyngbyapeptin analysis of Alyngbyapeptin C-(23) andis a linear N-terminal B modificationmodifiedindicated and peptide the di ff presenceered with by a containing of2 -substitutedtwo N,O other- dimethyltyrosine thiazole amino ring. acid In residues,comparison units in an between. toN lyngbyapeptin-methylvaline Structural unit,A ( analysis23 ) a, of lyngbyapeptinlyngbyapeptinthiazole- Bcontaining indicated B and modified C the possess presence alanine the same/similar of(Ala two-thz)N ,unit,O characteristic-dimethyltyrosine and a 3-methoxy C- and- 2 residues,N-butenoic-terminal acid an modificationN (Mba)-methylvaline moiety and unit, with the absolute stereochemistry S for the methylated amino acids. The structure of lyngbyapeptin a thiazole-containingdiffered by containingmodified other alanine amino (Ala-thz)acid units in unit, between. and a Structural 3-methoxy-2-butenoic analysis of lyngbyapeptin acid (Mba) B moiety C (24) differed from that of lyngbyapeptin B in having the presence of an N-terminal unit and with theindicated absolute the stereochemistry presence of twoS for N the,O-dimethyltyrosine methylated amino residues, acids. an The N- structuremethylvaline of lyngbyapeptin unit, a thiazole3-methoxy-containing-2-pentenoic modified acid (Mpa) alanine residue. (Ala-thz) The unit, structure and a of 3 -lyngbyapeptinmethoxy-2-butenoic D (27) acid differed (Mba) from moiety that 24 N C( ) diwithof fflyngbyapeptinered the absolute from that Astereochemistry (23 of) in lyngbyapeptin having SN for-Me the-Val methylated Bresidue in having instead amino theo facids. N presence-Me The-Ile sintructure addition of an of tolyngbyapept-terminal N-Me-Leu,in unita and 3-methoxy-2-pentenoicCthiazole (24) differed-containing from acid modified that (Mpa) of lyngbyapeptin proline residue. (Pro The- thz) B instructure unit having and theof N lyngbyapeptin, presenceO-dimethyltyrosine of an N D-terminal (27 (N),O di-diMe ff unitered- Tyr)and from that of lyngbyapeptin3[9-methoxy8,99]. Lyngbyabellin-2- Apentenoic (23) in acid having F (25 (Mpa)) andN -Me-Valresidue. I (26) areThe residue linearstructure dichlorinated instead of lyngbyapeptin of N lipopeptides-Me-Ile D (27 in) additiondifferedthat showed from to thatNthe-Me-Leu, a thiazole-containingofpresence lyngbyapeptin of two modified2,4 A -(disubstitut23) in having prolineed Nthiazole (Pro-thz)-Me-Val rings residue unit. Lyngbyabellin and insteadN,O o-dimethyltyrosinef N I- Me(26-)Ile and in additionF (25) w (N ereto,O N-diMe-Tyr)found-Me-Leu, to be a [98,99]. cytotoxic to human lung tumor and neuro-2a mouse neuroblastoma cells [100] (Figure 9). Lyngbyabellinthiazole- Fcontaining (25) and modified I (26) are proline linear dichlorinated (Pro-thz) unit andlipopeptides N,O-dimethyltyrosine that showed (N the,O-diMe presence-Tyr) of two [98,99]. Lyngbyabellin F (25) and I (26) are linear dichlorinated lipopeptides that showed the 2,4-disubstituted thiazole rings. Lyngbyabellin I (26) and F (25) were found to be cytotoxic to human presence of two 2,4-disubstituted thiazole rings. Lyngbyabellin I (O26) and F (25) were found to be lung tumorcytotoxic and to neuro-2a human lung mouse tumor neuroblastoma and neuroN -2a mouseO cells neuroblastoma [100] (Figure cells9). [100] (Figure 9). S N N N O O

N O O N O O

S N N N O 23 O

N Cl O O O Cl S O HO 23 O O O O N Cl O O N O O N O O Cl S N N O H HO O O O S H N O O O N O N O O N O O N O O O N O S N H N O O O S H N N OH O 24 N 25 O O O S O OH 24 25

Figure 9. Cont. Mar. Drugs 2020, 18, 11 of 42 Mar. Drugs 2020, 18, 329 11 of 43 Cl Mar. Drugs 2020, 18, 11 of 42 O Cl S S N HO Cl O O O N O O Cl N S S NO O HO N O O O O N O O N O O N O N N H OO O O N O O N H O N O O O O O N N O O N S O S O O

26 26 27 27 Figure 9.Figure Structures 9. Structures of lyngbyapeptinlyngbyapeptin of lyngbyapeptin A A( 23 (23) ) with with Pro-TzlPro--TzlTzl moiety moiety,moiety, lyngbyap, lyngbyapeptinlyngbyapeptine ptinC (24 ) C withAla ((24)) withAla-TzlwithAla-Tzl -Tzl moiety, lyngbyabellinmoiety,lyngbyabellin lyngbyabellin F F ( 25(25) F with) (with25) withα ,β,-dihydroxyisovaleric -,dihydroxyisovaleric-dihydroxyisovaleric acid acid acid (DHIV)-Tzl(DHIV) (DHIV)-Tzl- Tzlresidue residue, residue, lyngbyabellin lyngbyabellin, lyngbyabellin I I (26 I) with(26) with Val-Tzl(26 Val) with moiety,-Tzl Val moiety-Tzl and moiety, lyngbyapeptinand, and lyngbyapeptin lyngbyapeptin D (27 D) D with ( (2727) with Pro-Tzl Pro Pro-Tzl moiety.-Tzl moiety moiety. .

2.3. Structural Features of Thiazole (Tzl)- and Oxazole (Ozl)-Containing Cyclopeptides. 2.3. Structural F Featureseatures of T Thiazolehiazole ( (Tzl)-Tzl)- and OxazoleOxazole (Ozl)-Containing(Ozl)-Containing CyclopeptidesCyclopeptides. In addition to cyclic peptides with thiazole/thiazoline rings, mixed heterocyclic ring-based In addition to cyclic peptides with thiazole/thiazoline rings, mixed heterocyclic ring-based In cyclopeptides addition to are cyclic also derived peptides from with marine thiazole/thiazoline resources. Comoramide rings, A, didmolamide mixed heterocyclics A–C (28 – ring30), -based cyclopeptidesvemturamides are are alsoalso (31 derived,32 derived), dolastatins from from marine E marineand resources. I (34 resources.,35), microcyclamide Comoramide Comoramide (A36,) ,didmolamide bistratamides A, didmolamides s( 37A––41C) ,( 28– A–C30), (vemturamides28–30),raocyclamides vemturamides (31,32 )(,42 dolastatins, (4331),, 32tenuecyclamides,), dolastatins E and I E( patellamides34 and,35), I microcyclamide (34,, 35and), microcyclamide lissoclinamides (36), bistratamides are (36 ),bioactive bistratamides ( 37–41), (raocyclamides37–41),cyclo raocyclamidesoligo peptides(42,43), containing (42tenuecyclamides,,43), tenuecyclamides, thiazole and oxazole patellamides patellamides, rings. , and and lissoclinamides lissoclinamides are are bioactive cyclooligopeptidesComoramides containing are cyanobactins thiazole andthat oxazolecontained rings. prenylated amino acids. The ascidian-derived cyclooligocyclopeptidepeptides comoramidecontaining Athiazole was isolated and withoxazole threonine rings heterocyclized. in position 5 and prenylated Comoramides are cyanobactins that contained prenylated amino acids. The ascidian-derived Comoramidesin position 3 andare was cyanobactins found to contain that sixcontained amino acids prenylated in its structure amino, including acids. twoThe amino ascidian acids-derived cyclopeptidethat existed comoramide as a 5-methyl A wasoxazoline isolated (mOzn) with heterocycle threonine and heterocyclized as a thiazoline ring in position(Tzn). The 5 additional and prenylated in positionpositionamino 33 and and acid was was moieties found found present to to contain contain were six Lsix-alanine, amino amino acidsL -acidsphenylalanine in itsin structure,its structure, and L including-isoleucine., including two Like two amino patellin, amino acids acids that existedthat existed astrunkamide a 5-methyloxazolineas a 5- methylA, mollamideoxazoline (mOzn), and (mOzn)hexamollamide, heterocycle heterocycle andcomoramide as and a thiazoline as A a was thiazoline found ring (Tzn).to ring be a (Tzn Theunique additional). The type additional of amino peptide that contained lthreonine residuel for which the side chainl is modified as dimethylallyl ether. acidamino moieties acid moieties present were present-alanine, were L-phenylalanine,-alanine, L-phenylalanine and -isoleucine., and LikeL-isoleucine. patellin, trunkamide Like patellin, A, mollamide,This and cyclohexapeptide hexamollamide, exhibited comoramide structural A was found similarilty to be a with unique another type of peptideascidian-derived that contained trunkamidecycloheptapeptide A, mollamide mollamide, and hexamollamide, in two amino acids comoramide viz. Ile-Tzn andA was Phe -foundThr. Comoramide to be a unique A was type of threonine residue for which the side chain is modiﬁed as dimethylallyl ether. This cyclohexapeptide peptidefound that contained to be cytotoxic threonine against the residue A549, HT29for which, and MEL the -side28 tumor chain cell is lines modified [45]. as dimethylallyl ether. exhibitedThis cyclohexapeptide structuralDidmolamides similarilty A exhibitedand with B (28, another29) structuralare ascidian ascidian-derived -derived similarilty cyclohexapeptides cycloheptapeptide with another that contained mollamideascidian two-derived in two aminocycloheptapeptide acidsL-alanylthiazole viz. Ile-Tzn mollamide residues and Phe-Thr.and in two one L amino- Comoramidephenylalanine acids viz. moiety A wasIle -inTzn found comm and too n P be buthe cytotoxic- Thr. didmolamide Comoramide against A (28 the) A A549, was HT29,found andtocontain be MEL-28 cytotoxiced 5-methyloxazoline tumor against cell the lines A549, (mOzn) [45]. HT29 heterocycle, and MEL in addition,-28 tumor which cell islines replaced [45]. by L-threonine moiety in didmolamide B (29). Morover, didmolamide C (30) differs from didmolamides A and B Didmolamides A and B (28,,29)) areare ascidian-derived ascidian-derived cyclohexapeptides cyclohexapeptides that contained two l-alanylthiazole(28,29) in the residues oxidation and state one of l the-phenylalanine heterocyclic ring moietys, having in two common thiazoline but rings didmolamide (instead of A (28) L-alanylthiazolethiazoles) inresidues didmolamide and one C ( 30L)-.phenylalanine Additionally, didmolamide moiety in C comm (30) owasn but found didmolamide to contain a A (28) l containedcontainedmethyloxazole 5-methyloxazoline5-methyloxazoline ring instead (mOzn) (mOzn) of a methyloxazoline heterocycle heterocycle in ring addition, in of addition, didmolamide which which is A replaced (28 is). Didmolamide replaced by -threonine by A L (-28threonine) moiety inmoiety didmolamide displayedin didmolamide mild B (29 cyt).o toxicityB Morover, (29). againstMorover, didmolamide the A549, didmolamide HT29, C (and30) MEL28 diC ﬀ(30ers) tumor fromdiffers cell didmolamides from lines [didmolamides48,101] (Figure A and 10) BA. (and28,29 B) in the oxidation state of the heterocyclic rings, having two thiazoline rings (instead of thiazoles) (28,29) in the oxidationO state of the heterocyclicO rings, having two thiazolineS rings (instead of in didmolamide C (30). Additionally, didmolamide C (30) was found to contain a methyloxazole thiazoles) in didmolamide C (S30). Additionally, didmolamideS C (30) was found to contain a O O ring instead of a methyloxazolineN ring of didmolamideN A (28). DidmolamideN A (28) displayed mild methyloxazole ring insteadH of a methyloxazolineHO ringH of didmolamide NAH (28). Didmolamide A (28) N N O N NH HN cytotoxicitydisplayed mild against cyto thetoxicity A549, against HT29, the and A549, MEL28O HT29, tumor and cell MEL28 lines tumor [48,101 cell] (Figure lines [1048).,101] (Figure 10). N HN O HN O S O O NH NHO H S N N N N S S NO S O S O O N O N H HO H NH N N O N NH HN 28 O 29 30 N Figure 10. StructuresH Nof didmolamideO A (28) with Ala-Tzl moietHNies, didmolamideO B (29) with Ala-Tzl moietiesNH, and didmolamide C (30) with Ala-Tzn NmoietiesH . S H O N N N N

O S O S O 28 29 30

Figure 10. Structures of d didmolamideidmolamide A ( 28) with Ala Ala-Tzl-Tzl moieties,moieties, didmolamidedidmolamide B (29) with Ala-TzlAla-Tzl moieties,moieties, and didmolamidedidmolamide C (30)) with Ala-TznAla-Tzn moieties.moieties.

Mar. Drugs 2020, 18, 329 12 of 43 Mar. Drugs 2020, 18, 12 of 42 Mar. Drugs 2020, 18, 12 of 42 Venturamides (31,32) are cyanobacterium-derived thiazole- and methyloxazole-containing VenturVenturamidesamides (31,,32)) areare cyanobacterium-derived cyanobacterium-derived thiazole-thiazole- andand methyloxazole-containing methyloxazole-containing cyclohexapeptides that exhibited antimalarial and cytotoxic activities. Structural analysis of cyclohexapeptides that exhibited exhibited antimalarial antimalarial and and cytotoxic cytotoxic activities. activities. Structural Structural analysis of venturamide B (32) indicated the presence of D-alanine, D-valine, and D-allo-threonine in addition to venturamide B B ( (3232)) indicated indicated the the presence presence of of D-dalanine,-alanine, D-dvaline,-valine, and and D-dallo-allo-thr-threonineeonine in inaddition addition to three heteroaromatic moieties. The polypeptide venturamide B (32) was identified as threeto three heteroaromatic heteroaromatic moieties. moieties. The The polypeptide polypeptide venturamide venturamide B B(32 (32) )was was identified identiﬁed as cyclo-D-allo-Thr-Tzl-D-Val-Tzl-D-Ala-mOzl. The cyclic hexapeptide venturamide B (32) differed from cyclocyclo--Dd-allo-Thr-Tzl--Thr-Tzl-dD-Val-Tzl--Val-Tzl-dD-Ala-mOzl.-Ala-mOzl. The cyclic hexapeptide venturamide B ( (32) differ diﬀereded from venturamide A (31) in having a D-threonine unit in place of the D-alanine adjacent to the thiazole venturamide A ( 31) in having a dD-threonine-threonine unit in placeplace of the dD-alanine-alanine adjacent to the thiazole ring. There was a close similarity between the structures of venturamide A (31) and blue-green ringring.. There There was was a a close close similarity similarity between between the the structures structures of of venturamide A A ( 31) and blue-greenblue-green alga-derived cyclopeptide dendroamide A (33): however, D-valine and D-alanine are exchanged algaalga-derived-derived cyclopeptide cyclopeptide dendroamide dendroamide A A (33 (33):) however,: however,d-valine D-valine and andd-alanine D-alanine are exchanged are exchanged with with each other, adjacent to two thizaole heterocycles at C-12 and C-20. Venturamides (31,32) witheach other, each adjacent other, adja to twocent thizaole to two heterocycles thizaole heterocycles at C-12 and at C-20. C-12 Venturamides and C-20. Venturamides (31,32) showed ( strong31,32) showed strong in vitro activity against Plasmodium falciparum, with only mild cytotoxicity to showedin vitro activity strong against in vitroPlasmodium activity against falciparum Plasmodium, with only falciparum mild cytotoxicity, with only to mammalian mild cytotoxicity Vero cells. to mammalian Vero cells. Also, mild activity against Trypanasoma cruzi, Leishmania donovani, and Also,mammalian mild activity Vero against cells. Also,Trypanasoma mild activity cruzi, Leishmania against Trypanasoma donovani, and cruzi MCF-7, Leishmania cancer donovani cells was, alsoand MCF-7 cancer cells was also reported for venturamides [34] (Figure 11). MCFreported-7 cancer for venturamides cells was also [34 reported] (Figure for 11 venturamides). [34] (Figure 11).

O O O O O OH O S O N O OH N N S O HN O HN N N H S N S H N H H N S N S O N N N N O N N N NH NH NH HN O NH HN O O NH O NH NH N O N O O NH O NH NH N N O N O N

S S O S S O S S

31 32 33 31 32 33 Figure 11. Structures of venturamide A (31) with Ala-Tzl and Val-Tzl residues, venturamide B (32) Figure 11. Structures of v venturamideenturamide A A ( (3131)) with Ala Ala-Tzl-Tzl and and Val Val-Tzl-Tzl residues residues,, v venturamideenturamide B B ( (3232)) with Thr-Tzl and Val-Tzl residues, and dendroamide A (33) with Val-Tzl and Ala-Tzl residues. with Thr-TzlThr-Tzl and Val-TzlVal-Tzl residues,residues, andand dendroamidedendroamide AA ((3333)) withwith Val-TzlVal-Tzl and and Ala-Tzl Ala-Tzl residues. residues. The sea sea hare hare-derived-derived cyclo cyclopolypeptidespolypeptides dolastatin dolastatinss E and E and I (34 I,35 (34) ,w35ere) were found found to contain to contain three The sea hare-derived cyclopolypeptides dolastatins E and I (34,35) were found to contain three kindsthree kinds of five of-membered ﬁve-membered heterocycles heterocycles viz. oxazole viz. oxazole/methyloxazole/methyloxazole (Ozl/mOzl (Ozl/mOzl),), thiazole thiazole (Tzl),(Tzl), and kinds of five-membered heterocycles viz. oxazole/methyloxazole (Ozl/mOzl), thiazole (Tzl), and thiazoline/and thiazolineoxazoline/oxazoline (Tzn/(TznOzn)/Ozn),, in additi in additionon to one to one residue residue each each of ofD-dalanine-alanine and and Ll--alaninealanine and and one thiazoline/oxazoline (Tzn/Ozn), in addition to one residue each of D-alanine and L-alanine and one residue of ofd -isoleucineD-isoleucine in dolastatin in dolastatin E (34 E) while (34) onewhile residue one each residue of l -alanine, each of lL-valine,-alanine, and L-lvaline-isoleucine, and residue of D-isoleucine in dolastatin E (34) while one residue each of L-alanine, L-valine, and Lin-isoleucine the case of in dolastatin the case of I (dolastatin35). Although I (35) both. Although of these both cyclic of hexapeptidesthese cyclic hexapeptide displayed cytotoxicitys displayed L-isoleucine in the case of dolastatin I (35). Although both of these cyclic hexapeptides displayed cyagainsttotoxicity HeLa against S3 cells, HeLa in comparison, S3 cells, in dolastatincomparison, I (35 dolastatin) was found I (35 to) bewas more found cytotoxic to be more than dolastatincytotoxic cytotoxicity against HeLa S3 cells, in comparison, dolastatin I (35) was found to be more cytotoxic thanE[75 ,dolastatin76]. On the E other[75,76] hand,. On the in additionother hand, to twoin addition thiazole to (Tzl) two andthiazole one methyloxazole(Tzl) and one methyloxazole (mOzl) rings, than dolastatin E [75,76]. On the other hand, in addition to two thiazole (Tzl) and one methyloxazole (mOzl)the cyanobacterium-derived rings, the cyanobacterium cyclopeptide-derived microcyclamidecyclopeptide mic (rocyclamide36) contained (36 two) contain usualed amino two usualacids, (mOzl) rings, the cyanobacterium-derived cyclopeptide microcyclamide (36) contained two usual aminol-isoleucine acids, and Ll-isoleucine-alanine, and and one NL--methylhistidinealanine, and one residue. N-methylhistidine Overall, the hexapeptidic residue. structureOverall, was the amino acids, L-isoleucine and L-alanine, and one N-methylhistidine residue. Overall, the hexapeptidiccomposed of three structure units viz. was thiazole-methylhistidinyl, composed of three thiazole-isoleucinyl, units viz. thiazole and methyloxazole-alanyl-methylhistidinyl, hexapeptidic structure was composed of three units viz. thiazole-methylhistidinyl, thiazoleunits. This-isoleucinyl cyclic hexapeptide, and methyloxazole displayed- aalanyl moderate units cytotoxic. This cyclic activity hexapeptide against P388displayed murine a moderate leukemia thiazole-isoleucinyl, and methyloxazole-alanyl units. This cyclic hexapeptide displayed a moderate cytotoxiccells [35] (Figureactivity 12 against). P388 murine leukemia cells [35] (Figure 12). cytotoxic activity against P388 murine leukemia cells [35] (Figure 12).

O O S O O S O O N O O O N N N NH H O N N N NH S N H N NH N S N HN S N O NH HN O NH S N N NH NH N N O NH NH O N O H NH N N O N NH N H O N N O N N S NH O O S S N O O O S O O O 34 35 36 34 35 36 Figure 12. StructuresStructures of of d dolastatinolastatin E E ( (3434)) with with Ile Ile-Tzl-Tzl moiety, moiety, d dolastatinolastatin I I ( (3535)) with with Ala Ala-Tzl-Tzl moiety moiety,, Figure 12. Structures of dolastatin E (34) with Ile-Tzl moiety, dolastatin I (35) with Ala-Tzl moiety, and m microcyclamideicrocyclamide (36) with Ile-TzlIle-Tzl and N-Me-His-Tzl-Me-His-Tzl residues.residues. and microcyclamide (36) with Ile-Tzl and N-Me-His-Tzl residues.

MaMar.r. Drugs 2020, 1188, 329 13 of 4 432

The ascidian-derived bistratamide A and B contained heteroaromatic rings viz. methyloxazolineThe ascidian-derived (mOzn) and bistratamide thiazoline A (Tzn) and B rings contained in common heteroaromatic in addition rings to viz.one methyloxazolineresidue each of (mOzn)alanine, andphenylalanine thiazoline (Tzn), and ringsL-valin ine common. However, in additionbistratamide to one A residue differed each from of alanine,bistratamide phenylalanine, B only in theand conversionl-valine. However, of one thiazoline bistratamide ring to A dia thiazoleffered from, i.e., bistratamide these hexapeptides B only indiffered the conversion only by the of onethe presencethiazoline or ring absence to a thiazole, of one i.e.,double these bond hexapeptides. Both these diff eredcyclohexapeptides only by the the displayed presence or activity absence to ofward one humandouble bond.cell lines Both viz. these MRC5CV1 cyclohexapeptides fibroblasts displayedand T24 bladder activity carcinoma toward human cells. cell Bistratamides lines viz. MRC5CV1 C and D (fibroblasts37,38) possessed and T24 one bladder thiazole carcinoma ring in cells. common Bistratamides in addition C and to two D ( 37L-,valine38) possessed residues one. However thiazole, bistratamidering in common C (37 in) additiondiffered to from two bistratamidel-valine residues. D (38) However, in having bistratamide an L-alanine C moiety (37) diff insteadered from of additionalbistratamide L- Dvaline. (38) in Moreover, having an thel-alanine other moiety two heteroaromatic instead of additional rings inl-valine. bistratamideMoreover, D (38 the) otherwere methyloxazolinetwo heteroaromatic and rings oxazole in bistratamide, whereas in D bistratamide (38) were methyloxazoline C (37), oxazole and and oxazole, thiazole whereas rings were in present.bistratamide Bistratamides C (37), oxazole E and and F wer thiazolee found rings to were contain present. three Bistratamides residues of L E-valine and F in were addition found to thiazolecontain three and residues methyloxazoline of l-valine rings. in addition Bistratamide to thiazole F differed and methyloxazoline from bistratamide rings. E Bistratamide in having an F additionaldiffered from oxazoline bistratamide ring E insteadin having of an a additional second thiazoleoxazoline ring ring instead in bistratamide of a second E. thiazole Similarily, ring binistratamid bistratamidees G E.and Similarily, H (39,40) bistratamides were found to G contain and H three (39,40 residues) were found of L-valine to contain in addition three residuesto thiazole of andl-valine methyloxazole in addition to rings. thiazole Bistratamide and methyloxazole G (39) rings.differed Bistratamide from bistratamide G (39) diff ered H (40 from) in bistratamide having an additionalH(40) in having oxazole an additional ring instead oxazole of a ring second instead thiazole of a second ring thiazole in bistratamid ring ine bistratamide H (40). Further, H (40). bistratamideFurther, bistratamide I (41) contained I (41) contained three residues three residuesof L-valine of lin-valine addition in addition to one thiazole to one thiazoleand one andoxazole one ring.oxazole The ring. ascidian The ascidian-derived-derived bistratamide bistratamidess M and M and N ( N46 (,4746),47 are) are oxazole oxazole-thiazole-containing-thiazole-containing cyclic hexapeptides thatthat displayed displayed moderate moderate cytotoxicity cytotoxicity against against four four human human tumor tumor cell lines cell includinglines including NSLC A-549NSLC humanA-549 human lung carcinoma lung carcinoma cells, MDA-MB-231 cells, MDA-MB human-231 human breast adenocarcinomabreast adenocarcinoma cells, HT-29 cells, humanHT-29 humancolorectal colorectal carcinoma carcinoma cells, and PSN1 cells, human and PSN1 pancreatic human carcinoma pancreatic cells. carcinoma Moreover, bistratamides cells. Moreover, G-I (b39istratamides–41) and J G showed-I (39–41 weak) and J to showed moderate weak activity to moderate against activity the HCT-116 against the human HCT- colon116 human tumor colon cell tumorline [50 cell,59– line61] (Figure[50,59– 6113]). (Figure 13).

O O O

N S N NH H S N N S NH N O NH O NH N NH N O O O O

37 38

O O O O O S N N N H HO H H N N N NH O N O N O

HN O HN O HN O NH NH NH N N N

O O S S O S 39 40 41

Figure 13. Structures ofof bistratamide bistratamide C C (37 (37) with) with Val-Tzl Val-Tzl and and Ala-Tzl Ala-Tzl residues, residues bistratamide, bistratamide D (38 D) with(38) Val-Tzlwith Val moiety,-Tzl moiety, bistratamide bistratamide G (39) G with (39 Val-Tzl) with Val moiety,-Tzl moiety, bistratamide bistratamide H (40) with H (40 two) with Val-Tzl two residues, Val-Tzl residues,and bistratamide and bistratamide I (41) with I Val-Tzl(41) with moiety. Val-Tzl moiety.

Raocyclamides ( 42,,43)) are cyclooligopeptidescyclooligopeptides in which the ring system contains amide links onlyonly,, and they contain three heteroaromaticheteroaromatic rings symmetrically arranged in a peptide chain with differentdiﬀerent connected aliphatic amino acids providing structural diversity. Raocyclamides A and B (42,43) areare cyanobacterium-derived cyanobacterium-derived oxazoleoxazole andthiazole-containingand thiazole-containing cyclic hexapeptides cyclic hexapeptides with cytotoxic with cytotoxic properties. Raocyclamide A (42) contained three standard amino acid residues viz.

Mar. Drugs 2020, 18, 329 14 of 43

Mar. Drugs 2020, 18, 14 of 42 properties. Raocyclamide A (42) contained three standard amino acid residues viz. d-isoleucine, lD-alanine,-isoleucine, and L-dalanine,-phenylalanine and D-phenylalanine and three modified and three amino modified acids viz. amino thiazole, acids oxazole, viz. thiazole, and oxazoline. oxazole, Inand comparison, oxazoline. In raocyclamide comparison, Braocyclamide (43) contained B ( four43) contained standard four amino standard acid residues amino acid viz. dresidues-isoleucine, viz. lD-alanine,-isoleucine,d-phenylalanine, L-alanine, D-phenylalanine and d-serine, and twoD-serin modifiede and two amino modified acids viz.amino thiazole acids andviz. oxazole.thiazole Raocyclamideand oxazole. R Aaocyclamide (42) differed A from (42) raocyclamidediffered from B raocyclamide (43) in having B an (43 additional) in having heterocyclic an additional ring “oxazoline”heterocyclic withring a“oxazolined-configuration” with instead a D-configuration of a d-serine instead residue. of Raocyclamidea D-serine residue. A (42 )Raocyclamide was found to beA moderately(42) was found cytotoxic to be moderately against sea cytotoxic urchin embryos against [ 32sea] (Figureurchin embryos14). [32] (Figure 14).

O O

S N S N H H N O N O OH N HN NH NH

O NH O NH N N O O O O 42 43

Figure 14. StructuresStructures of r raocyclamideaocyclamide A ( 42) and r raocyclamideaocyclamide B ( 43) with dD-Ile-Tzl-Ile-Tzl residues.residues.

TheThe ascidian-derivedascidian-derived lissoclinamideslissoclinamides 1–101–10 and and cyanobacterium-derived cyanobacterium-derived tenuecyclamide tenuecyclamide A A and and B areB are other other cyclopolypeptides cyclopolypeptides containing containing thiazole, thiazole, thiazoline, thiazoline, methyloxazole, methyloxazole and, methyloxazolineand methyloxazoline rings whichrings which displayed displayed cytotoxicity cytotoxicity against against SV40 transformed SV40 transformed ﬁbroblasts fibrobla and transitionalsts and transitional bladder carcinoma bladder cellscarcinoma as well cells as inhibited as well as the inhibited division the of division sea urchin of embryossea urchin [102 embryos–105]. [102–105]. Various heterocyclicheterocyclic marine-derivedmarine-derived thiazole-basedthiazole-based cyclopolypeptides including those having thiazoline (Tzn), oxazole (Ozl), (Ozl), oxazoline oxazoline (Ozn), (Ozn), 5-methyloxazole 5-methyloxazole (mOzl), (mOzl), 5-methyloxazoline 5-methyloxazoline (mOzn), 5-hydroxytryptophan5-hydroxytryptophan (Htrp), N N-methylimidazole-methylimidazole (mImz), histidine histidine (His), (His), tryptophan tryptophan (Trp), (Trp), 2-bromo-5-hydroxytryptophan2-bromo-5-hydroxytryptophan (Bhtrp), (Bhtrp), and and N-methyltryptophan N-methyltryptophan (Metrp) (Metrp) rings in rings addition in addition to thiazole, to togetherthiazole, withtogether their with molecular their m formulasolecular formulas and composition, and composition are tabulated, are tabulated in Table1 .in Table 1.

Table 1. Heterocyclic thiazole thiazole-based-based cyclopolypeptides from marine resources.resources. Molecular Heterocyclic Year Cyclic Peptide Composition Heterocyclic Year Cyclic Peptide MolecularFormula Formula Composition Ring (s) * Ring (s) * 1980 Ulicyclamide [53]C H N O S cyclooligopeptide Tzl, mOzn 1980 Ulicyclamide [53] C33H3933N739O5S72 5 2 cyclooligopeptide Tzl, mOzn 1980 1980Ulithiacyclamide Ulithiacyclamide [53] [53]CC32H4232NH842ON6S84O 6S4 bicyclicbicyclic peptide peptide Tzl, mOznTzl, mOzn

1982 1982Patellamide Patellamide A [39] A [39]CC35H5035NH850ON6S82O 6S2 cyclooctapeptidecyclooctapeptide Tzl, Ozn,Tzl, mOzn Ozn, mOzn

1982 1982Patellamide Patellamide B [39] B [39]CC38H4838NH848ON6S82O 6S2 cyclooctapeptidecyclooctapeptide Tzl, mOznTzl, mOzn 1982 Patellamide C [39] C37H46N8O6S2 cyclooctapeptide Tzl, mOzn 1982 Patellamide C [39]C37H46N8O6S2 cyclooctapeptide Tzl, mOzn 1983 Ascidiacyclamide [106] C36H52N8O6S2 cyclopolypeptide Tzl, mOzn 1983 Ascidiacyclamide [106]C36H52N8O6S2 cyclopolypeptide Tzl, mOzn 1989 Lissoclinamide 4 [56] C38H43N7O5S2 cycloheptapeptide Tzl, Tzn, mOzn 1989 Lissoclinamide 4 [56]C38H43N7O5S2 cycloheptapeptide Tzl, Tzn, mOzn 1989 Lissoclinamide 5 [56] C38H41N7O5S2 cycloheptapeptide Tzl, mOzn 1989 Lissoclinamide 5 [56]C H N O S cycloheptapeptide Tzl, mOzn 1989 Ulithiacyclamide B [57] C35H4038N841O6S74 5 2 bicycle peptide Tzl, mOzn 1989 1989Patellamide Ulithiacyclamide D [80] B [57]CC38H4835NH840ON6S82O 6S4 bicyclecyclooctapeptide peptide Tzl, mOznTzl, mOzn

1990 1989Lissoclinamide Patellamide 8 [55] D [80]CC38H4338NH748ON5S82O 6S2 cyclooctapeptidecycloheptapeptide Tzl,Tzl, mOzn Tzn, mOzn

1990 1990Lissoclinamide Lissoclinamide 7 [55] 8 [55]CC38H4538NH743ON5S72O 5S2 cycloheptapeptidecycloheptapeptide Tzl, Tzn,Tzn, mOzn mOzn 1992 Tawicyclamide A [41] C39H51N8O5S3 cyclooctapeptide Tzl, Tzn 1990 Lissoclinamide 7 [55]C38H45N7O5S2 cycloheptapeptide Tzn, mOzn 1992 Tawicyclamide B [41] C36H53N8O5S3 cyclooctapeptide Tzl, Tzn 1992 Tawicyclamide A [41]C39H51N8O5S3 cyclooctapeptide Tzl, Tzn 1992 Patellamide E [58] C39H50N8O6S2 cyclooctapeptide Tzl, mOzn 1992 Tawicyclamide B [41]C36H53N8O5S3 cyclooctapeptide Tzl, Tzn 1992 Bistratamide C [59] C22H26N6O4S2 cyclohexapeptide Tzl, Ozl 1992 Patellamide E [58]C39H50N8O6S2 cyclooctapeptide Tzl, mOzn 1992 Bistratamide D [59] C25H34N6O5S cyclohexapeptide Tzl, Ozl, mOzn 1995 1992Keramamide Bistratamide J [67] C [59]CC33H5822NH1026ON116SO 4S2 cyclohexapeptidecyclopolypeptide Tzl, OzlTzl, Trp 1995 Keramamide G [67] C43H56N10O11S cyclopolypeptide Tzl, Htrp 1995 Keramamide H [67] C43H57N10O12BrS cyclopolypeptide Tzl, Bhtrp 1995 Cyclodidemnamide [62] C34H43N7O5S2 cycloheptapeptide Tzl, Tzn, Ozn 1995 Dolastatin E [76] C21H26N6O4S2 cyclohexapeptide Tzl, Tzn, Ozl

Mar. Drugs 2020, 18, 329 15 of 43

Table 1. Cont.

Molecular Heterocyclic Year Cyclic Peptide Composition Formula Ring (s) *

1992 Bistratamide D [59]C25H34N6O5S cyclohexapeptide Tzl, Ozl, mOzn

1995 Keramamide J [67]C33H58N10O11S cyclopolypeptide Tzl, Trp

1995 Keramamide G [67]C43H56N10O11S cyclopolypeptide Tzl, Htrp

1995 Keramamide H [67]C43H57N10O12BrS cyclopolypeptide Tzl, Bhtrp

1995 Cyclodidemnamide [62]C34H43N7O5S2 cycloheptapeptide Tzl, Tzn, Ozn

1995 Dolastatin E [76]C21H26N6O4S2 cyclohexapeptide Tzl, Tzn, Ozl

1995 Lissoclinamide 3 [54]C33H41N7O5S2 cycloheptapeptide Tzl, mOzn

1995 Patellamide F [54]C37H46N8O6S2 cyclooctapeptide Tzl, Ozn, mOzn

1995 Nostocyclamide [107]C27H32N6O6S cyclohexapeptide Tzl, mOzl

1996 Waiakeamide [66,108]C37H49N7O8S3 cyclohexapeptide Tzl

1996 Raocyclamide B [32]C27H32N6O6S cyclohexapeptide Tzl, Ozl

1996 Raocyclamide A [32]C27H30N6O5S cyclohexapeptide Tzl, Ozl, Ozn

1996 Dendramide A [40]C21H24N6O4S2 cyclohexapeptide Tzl, mOzl

1996 Dendramide B [40]C21H24N6O4S3 cyclohexapeptide Tzl, mOzl

1996 Dendramide C [40]C21H24N6O5S3 cyclohexapeptide Tzl, mOzl

1997 Oriamide [65]C44H54N15O9S2Na cyclopolypeptide Tzl

1997 Dolastatin I [75]C24H32N6O5S cyclohexapeptide Tzl, mOzl, Ozn

1998 Ulithiacyclamide E [51]C35H44N8O8S4 bicyclic peptide Tzl

1998 Comoramide B [45]C34H50N6O7S cyclohexapeptide Tzn

1998 Mayotamide A [45]C30H43N7O4S4 cycloheptapeptide Tzl, Tzn

1998 Mayotamide B [45]C29H41N7O4S4 cycloheptapeptide Tzl, Tzn

1998 Keramamide K [109]C44H60N10O11S cyclopolypeptide Tzl, Metrp

1998 Ulithiacyclamide F [51]C35H42N8O7S4 bicycle peptide Tzl, mOzn

1998 Ulithiacyclamide G [51]C35H42N8O7S4 bicycle peptide Tzl, mOzn

1998 Comoramide A [45]C34H48N6O6S cyclohexapeptide Tzn, mOzn

1998 Patellamide G [51]C38H50N8O7S2 cyclooctapeptide Tzl, mOzn

1998 Tenuecyclamide A [105]C19H20N6O4S2 cyclohexapeptide Tzl, mOzl

1998 Tenuecyclamide C [105]C20H22N6O4S3 cyclohexapeptide Tzl, mOzl

1998 Tenuecyclamide D [105]C20H22N6O5S3 cyclohexapeptide Tzl, mOzl

2000 Haligramide A [63]C37H49N7O6S cyclohexapeptide Tzl

2000 Haligramide B [63]C37H49N7O7S cyclohexapeptide Tzl

2000 Dolastatin 3 [9]C25H36N6O5S2 cyclopentapeptide Tzl

2000 Homodolastatin 3 [9]C30H42N8O6S2 cyclopentapeptide Tzl

2000 Lyngbyabellin A [27]C29H40N4O7S2Cl2 cyclodepsipeptide Tzl

2000 Lyngbyabellin B [86]C28H40N4O7S2Cl2 cyclodepsipeptide Tzl, Tzn

2000 Kororamide [9]C45H64N10O10S2 cyclononapeptide Tzl, Tzn

2000 Lissoclinamide 9 [52]C35H45N7O5S2 cycloheptapeptide Tzl, Tzn, mOzn

2000 Ceratospongamide [77]C41H49N7O6S cycloheptapeptide Tzl, mOzn

2000 Microcyclamide [35]C26H30N8O4S2 cyclohexapeptide Tzl, mOzl, mImz

2001 Nostocyclamide M [36]C20H22N6O4S3 cyclohexapeptide Tzl, mOzl

2002 Cyclodidemnamide B [42]C32H47N7O6S2 cycloheptapeptide Tzl

2002 Obyanamide [12]C30H41N5O6S cyclodepsipeptide Tzl

2002 Ulongamide A [13]C32H45N5O6S cyclodepsipeptide Tzl

2002 Ulongamide D [13]C34H49N5O7S cyclodepsipeptide Tzl

2002 Ulongamide E [13]C35H51N5O7S cyclodepsipeptide Tzl

2002 Ulongamide B [13]C32H45N5O7S cyclodepsipeptide Tzl Mar. Drugs 2020, 18, 329 16 of 43

Table 1. Cont.

Molecular Heterocyclic Year Cyclic Peptide Composition Formula Ring (s) *

2002 Ulongamide C [13]C36H45N5O7S cyclodepsipeptide Tzl

2002 Ulongamide F [13]C30H49N5O6S cyclodepsipeptide Tzl

2002 Banyascyclamide B [11]C22H30N6O5S2 cyclohexapeptide Tzl

2002 Banyascyclamide C [11]C25H28N6O5S2 cyclohexapeptide Tzl

2002 Banyascyclamide A [11]C25H26N6O4S2 cyclohexapeptide Tzl, mOzn

2002 Leucamide A [70]C29H37N7O6S cycloheptapeptide Tzl, Ozl, mOzl

2003 Guineamide A [14]C31H44N5O6S cyclodepsipeptide Tzl

2003 Guineamide B [14]C32H45N5O6S cyclodepsipeptide Tzl

2003 Didmolamide A [48]C25H26N6O4S2 cyclohexapeptide Tzl

2003 Didmolamide B [48]C25H28N6O5S2 cyclohexapeptide Tzl

2003 Bistratamide J [50]C25H36N6O5S2 cyclohexapeptide Tzl

2003 Bistratamide I [50]C25H36N6O5S2 cyclohexapeptide Tzl, Ozl

2003 Bistratamide H [50]C25H32N6O4S2 cyclohexapeptide Tzl, mOzl

2003 Bistratamide E [50]C25H34N6O4S2 cyclohexapeptide Tzl, mOzn

2003 Bistratamide G [50]C25H32N6O5S cyclohexapeptide Tzl, Ozl, mOzl

2003 Bistratamide F [50]C26H36N6O5S cyclohexapeptide Tzl, Ozn, mOzn

2003 Myriastramide C [69]C42H53N9O7S cyclooctapeptide Tzl, Ozl, Trp

2003 Bistratamide B [60]C27H32N6O4S2 cyclohexapeptide Tzl, Tzn, mOzn

2004 Scleritodermin A [64]C42H54N7O10SNa cyclopolypeptide Tzl

2005 Lyngbyabellin E [28]C37H51N3O12S2Cl2 cyclodepsipeptide Tzl

2005 Lyngbyabellin H [28]C37H51N3O11S2Cl2 cyclodepsipeptide Tzl

2005 Mechercharmycin A [79]C35H32N8O7S cyclooligopeptide Tzl, Ozl

2006 Trichamide [17]C44H66N16O12S2 cyclopolypeptide Tzl, His

2007 Urukthapelstatin A [78]C34H30N8O6S2 cyclooligopeptide Tzl, Ozl

2007 Venturamide A [34]C21H24N6O4S2 cyclohexapeptide Tzl, mOzl

2007 Venturamide B [34]C22H26N6O5S2 cyclohexapeptide Tzl, mOzl

2008 Mollamide C [46]C30H46N6O6S cyclohexapeptide Tzl

2008 Aerucyclamide B [37]C24H33N6O4S2 cyclohexapeptide Tzl, mOzn

2008 Aerucyclamide A [37]C24H34N6O4S2 cyclohexapeptide Tzl, Tzn, mOzn

2008 Aerucyclamide D [38]C26H31N6O4S3 cyclohexapeptide Tzl, Tzn, mOzn

2008 Aerucyclamide C [38]C24H32N6O5S cyclohexapeptide Tzl, Ozl, mOzn

2009 Sanguinamide A [73]C37H52N7O6S cycloheptapeptide Tzl

2009 Sanguinamide B [73]C33H43N8O6S2 cyclooctapeptide Tzl, Ozl

2010 Microcyclamide MZ602 [18]C28H38N6O7S cyclohexapeptide Tzl

2010 Microcyclamide MZ568 [18]C25H40N6O7S cyclohexapeptide Tzl

2010 Aeruginazole A [91]C53H66N13O11S3 cyclododecapeptide Tzl

2010 Lyngbyabellin J [30]C37H51N3O12S2Cl2 cyclodepsipeptide Tzl

2010 27-deoxylyngbyabellin A [30]C29H40N4O6S2Cl2 cyclodepsipeptide Tzl

2012 Aeruginazole DA1497 [8] C68H91N17NaO14S4 cyclopolypeptide Tzl

2012 Aeruginazole DA1304 [8] C61H72N14NaO13S3 cyclopolypeptide Tzl

2012 Aeruginazole DA1274 [8] C60H70N14NaO12S3 cyclopolypeptide Tzl

2012 Lyngbyabellin N [29]C40H58N4O11S2Cl2 cyclodepsipeptide Tzl

2012 Largazole [16]C29H38N4O5S3 cyclodepsipeptide Tzl, Tzn

2012 Marthiapeptide A [74]C30H31N7O3S4 cyclooligopeptide Tzl, Tzn

2012 Calyxamide A [110]C45H61N11O12S cyclooligopeptide Tzl, Htrp Mar. Drugs 2020, 18, 329 17 of 43

Table 1. Cont.

Molecular Heterocyclic Year Cyclic Peptide Composition Formula Ring (s) *

2012 Calyxamide B [110]C45H61N11O12S cyclooligopeptide Tzl, Htrp

2013 Aestuaramide A [10]C40H51N7O6S3 cyclopolypeptide Tzl

2013 Aestuaramide B [10]C35H43N7O6S3 cyclopolypeptide Tzl

2013 Aestuaramide C [10]C40H51N7O6S3 cyclopolypeptide Tzl

2014 Balgacyclamide A [33]C25H37N6O5S cyclooligopeptide Tzl, mOzn

2014 Balgacyclamide B [33]C25H39N6O6S cyclooligopeptide Tzl, mOzn

2014 Balgacyclamide C [33]C28H37N6O6S cyclooligopeptide Tzl, mOzn

2016 Jamaicensamide A [89]C45H61N9O10S cyclooligopeptide Tzl, Htrp

2017 Cyclotheonellazole A [68] C44H54N9O14S2Na2 cyclopolypeptide Tzl

2017 Cyclotheonellazole B [68]C45H57N9O14S2Na cyclopolypeptide Tzl

2017 Cyclotheonellazole C [68] C43H52N9O14S2Na2 cyclopolypeptide Tzl

2017 Bistratamide M, N [61]C21H24N6O4S2 cyclohexapeptide Tzl, Ozl * Tzl: Thiazole, Tzn: Thiazoline, Ozl: Oxazole, Ozn: Oxazoline, mOzl: 5-methyloxazole, mOzn: 5-methyloxazoline, Htrp: 5-hydroxytryptophan, mImz: N-methylimidazole, His: histidine, Trp: tryptophan, Bhtrp: 2-bromo-5-hydroxytryptophan, Metrp: N-methyltryptophan.

2.4. Structural Features of Thiopeptide Antibiotics Thiopeptides are a novel family of antibiotics which are associated with a lot of pharmacological properties including immunosuppressive, antineoplastic, antimalarial, and potent antimicrobial activity against Gram-positive bacteria. Due to their interesting structures and bioprofile against bacteria, thiopeptides have attracted the attention of researchers and scientists as a new class of emerging antibiotics. The most important characteristic feature of the thiopeptides is the central nitrogen-containing six-membered ring with diverse oxidation states. On the basis of different oxidation states of the central ring of thiopeptides, they can belong to the “a series” with a totally reduced central piperidine, the “b series” with a 1,2-dehydropiperidine ring, and the “c series” with a piperidine ring fused with imidazoline. All members of series a, b, and c have a macrocycle which contains a quinaldic acid moiety. The d series shows a trisubstituted pyridine ring, and the e series is known for the hydroxyl group in the central tetrasubstituted pyridine ring. The e series also presents a macrocycle formed by a modified 3,4-dimethylindolic acid moiety. The central ring in thiopeptides serves as a scaffold to at least one macrocycle and a tail, containing different thiazoles and oxazoles which are developed by dehydration/dehydrosulfanylation of amino acid like serine, cysteine, etc. TP-1161, YM-266183, YM-266184, kocurin, baringolin, geninthiocin, Ala-geninthiocin, and Val-geninthiocin are examples of thiopeptides from marine resources [111]. TP-1161 belongs to the “d series” of thiopeptide antibiotics, produced by a marine sediment-derived Nocardiopsis sp. Structural features of this thiopeptide include the three 2,4-disubstituted thiazoles and one 2,4-disubstituted oxazole moiety in addition to the presence of a trisubstitued pyridine (Pyr) functional unit and an unusual aminoacetone moiety. TP-1161 displayed good activity against a panel of Gram-positive bacteria including Staphylococcus aureus, Staphylococcus haemolyticus, Staphylococcus epidermidis, Enterococcus faecium, and Enterococcus faecalis [112]. YM-266183 and YM-266184 are novel thiopeptide antibiotics produced by Bacillus cereus isolated from a marine sponge and structurally related to a known family of antibiotics that include thiocillins and micrococcins. Structural analysis of these thiopeptides indicated the presence of several unusual amino acids with heteroaromatic moieties, including the six thiazole rings, a 2,3,6-trisubstituted pyridine residue to which three of thiazole units are attached, a 2-amino-2-butanoic acid unit with an aminoacetone residue, a (Z)-2-amino-2-butenoic acid unit attached to a threonine residue, and a 3-hydroxyvaline moiety. There was a close similarity in structures of YM-266183 and YM-266184 except for the presence of a methoxy group (C55) in YM-266184 instead of the hydroxy group of Mar. Drugs 2020, 18, 329 18 of 43

YM-266183. These new antibacterial substances were found to exhibit activity against drug-resistant bacteria [113]. Kocurin is a new anti-methicillin-resistant Staphylococcus aureus (MRSA) bioactive compound, belonging to the thiazolyl peptide family of antibiotics, obtained from sponge-derived Kocuria and Micrococcus spp. Structural analysis of this thiopeptide indicated the presence of several heteroaromatic moieties, including one thiazoline and four thiazole rings, one methyloxazole ring and a 2,3,6-trisubstituted pyridine residue to which two of thiazole units and one methyloxazole unit are attached, aromatic amino acids like phenylalanine and tyrosine, and two proline units. Kocurin was found to be closely related to two known thiazolyl peptide antibiotics with similar modes of action: GE37468A and GE2270. The antimicrobial activity profile of kocurin indicated the extreme potency against Gram-positive bacteria with minimum inhibitory concentration (MIC) values of 0.25–0.5 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA) [114]. Baringolin is a novel thiopeptide of the d series, containing a central 2,3,6-trisubstituted pyridine, derived from fermentation of the marine-derived bacterium Kucuria sp. The macrocycle in baringolin contained three thiazoles—a methyloxazole and pyridine ring, a thiazoline ring with an α-chiral center, and a pyrrolidine motif derived from a proline residue—in addition to three natural amino acids viz. tyrosine, phenylalanine, and asparagine. The long peptidic tail was found to be a pentapeptide containing three methylidenes resulting from dehydration of serine that is attached to the pyridine through a fourth thiazole. This thiopeptide displayed important antibacterial activity against Staphylococcus aureus, Micrococcus luteus, Propionibacterium acnes, and Bacillus subtilis at nanomolar concentrations [115]. Ala-geninthiocin, geninthiocin, and Val-geninthiocin are new broad-spectrum thiopeptide antibiotics produced from the cultured marine Streptomyces sp. Structural analysis of all three thiopeptides indicated the presence of heteroaromatic moieties, including one thiazole and two oxazole rings, one methyloxazole ring, and a 2,3,6-trisubstituted pyridine residue to which two of thiazole units are attached at the 2 and 3 positions, including proteinogenic amino acid viz. l-threonine. The peptide structure of Ala-geninthiocin is largely similar to geninthiocin, the only difference being the presence of an l-Alanine residue instead of dealanine at the C-terminal amide. Further, Val-geninthiocin contained l-valine moiety instead of l-hydroxyvaline of geninthiocin. Ala-geninthiocin was found to exhibit good activity against Gram-positive bacteria including Staphylococcus aureus, Bacillus subtilis, Mycobacterium smegmatis, and Micrococcus luteus as well as cytotoxicity against A549 human lung carcinoma cells. When compared to geninthiocin, Ala-geninthiocin displayed better cytotoxicity but antibiotic activity against Gram-positive bacteria was comparatively low. Val-geninthiocin was found to possess more antifungal activity against Mucor hiemalis and cytotoxicity against A549 human lung carcinoma cells and L929 murine fibrosarcoma in comparison to geninthiocin. Further, Ala-geninthiocin and Val-geninthiocin displayed weak to moderate antifungal activity against Candida albicans, whereas geninthiocin was inactive. Ala-geninthiocin and geninthiocin displayed moderate antibiotic activity against Gram-negative bacteria Chromobacterium violaceum, whereas val-geninthiocin was inactive [116].

2.5. Structural Features of Bridged Heterocyclic Peptide Bicycles Bicyclic peptides form one of the promising platforms for drug development owing to their biocompatibility and chemical diversity to proteins. Bioactive bicyclic peptides exist as disulfide-bridged peptide bicycles (e.g., ulithiacyclamide A, B, E, F, and G), histidino-tyrosine bridged peptide bicycles (e.g., aciculitins A–C), histidino-alanine bridged peptide bicycles (e.g., Theonellamides A, B, C, F, and G and Theogrenamide) and are derived from marine sponges/tunicates, plants, and mushrooms. Ulithiacyclamide A is a strong cytotoxic disulfide-bridged peptide bicycle characterized by a symmetrical dimeric structure consisting of oxazoline and thiazole rings in addition to a transannular disulfide isolated from marine tunicate/ascidian Lissoclinum patella. The structure of ulithiacyclamide B Mar. Drugs 2020, 18, 329 19 of 43 closely resembled the structure of ulithiacyclamide with the exception of the replacement of one of the two d-leucine units with d-phenylalanine residue, resulting in an asymmetrical dimeric structure. Because the configuration of both leucine and phenylalanine was d, both thiazole amino acids possessed R configurations in ulithiacyclamide. The structures of ulithiacyclamides E, F, and G are related in structure to ulithiacyclamide B but with either both (in the case of ulithiacyclamide E) or just one of the two (in the cases of ulithiacyclamides F and G) oxazoline rings existing as their hydrolyzed l-threonine counterpart. Ulithiacyclamides F and G were found to be isomers and contained one oxazoline including one “free” threonine unit and were anhydro forms of ulithiacyclamide E. Ulithiacyclamide and ulithiacyclamide B exhibited cytotoxicity against the KB cell line with IC50 values of 35 and 17 ng/mL, respectively [51,53,56,57,117]. Aciculitins A–C are cytotoxic and antifungal glycopeptidolipids from the lithistid sponge Aciculites orientalis. They consist of a bicyclic peptide structure that contains a histidine-tyrosine bridge, with an unusual combination of tyrosine and histidine residues joined through the 30-position of tyrosine and the 50-position of histidine [118]. Theonegramide is a peculiar antifungal peptide that presents an intra-cycle histidine-alanine bridge in which the imidazole ring is substituted by a d-arabinose moiety. The alanine portion of histidinoalanine was found to have the (R)-configuration while the histidine portion with the (S)-configuration [119]. Theonellamides (TNMs) are members of a distinctive family of sterol-binding bioactive bicyclic dodecapeptides, with theonellamide F being a novel antifungal bicyclic dodecapeptide with an unprecedented histidinoalanine bridge composed of unusual amino acid residues like τ-l-histidino-d-alanine, (2S,4R)-2-amino-4-hydroxyadipic acid (Ahad), and (3S,4S,5E,7E)-3-amino-4-hydroxy-6-methyl-8- (p-bromophenyl)-5,7-octadienoic acid (Aboa). Theonellamide F was found to be a useful agent for investigating membrane structures in cells and inhibited growth of various pathogenic fungi including Candida sp., Trichophyton sp., and Aspergillus sp. [120,121]. Moroidin is a unique bicyclic peptide bearing residues like histidine, tryptophan, arginine, and β-leucine, isolated from the seeds of the Chinese herb Celosia argentea (Amaranthaceae), that remarkably inhibited the polymerization of tubulin [122]. Celogentins are unique cyclopolypeptides containing a bicyclic ring system; an unusual C–N bond formed by Trp and His residues; and an unusual amino acid, β-substituted Leu, isolated from the seeds of Celosia argentea. Celogentins A–C inhibited the polymerization of tubulin, and celogentin C was found to be 4 times more potent than moroidin in the inhibitory activity [123]. Phalloidin is a rigid bicyclic peptide containing an unusual cysteine-tryptophan linkage, isolated from the death cap mushroom Amanita phalloides. This cycloheptapeptide is commonly used in imaging applications to selectively label F-actin in fixed cells, permeabilized cells, and cell-free experiments [124]. α-Amanitin is a highly toxic hydrophobic bicyclic octapeptide found in a genus of mushrooms known as Amanita, including Amanita phalloides, Amanita verna, and Amanita virosa. The cytotoxicity found in amanitin is the result of inhibition of RNA polymerases, in particular RNA polymerase II, which precludes mRNA synthesis [124].

2.6. Structural Features of Other Heterocyclic Peptides from Marine Resources Azonazine is a unique anti-inflammatory peptide with a macrocyclic heterocyclic core of the benzofuro indole ring system with diketopiperazine residue and possesses structural similarity with diazonamide A. The absolute configuration of this marine sediment-derived fungus-originated complex peptide was established as 2R,10R,11S,19R. The first total synthesis of hexacyclic dipeptide ent-( )-azonazine was accomplished using a hypervalent iodine-mediated biomimetic oxidative − cyclization to construct the highly strained core [125]. The pyridine ring (in the form of 3-hydroxypicolinic acid, 3HyPic) also forms part of cyclopeptide structures such as fijimycins and etamycin. Fijimycins A–C are cyclic depsipeptides from a marine-derived Streptomyces sp. which possessed in vitro antibacterial activity against three methicillin-resistant Staphylococcus aureus (MRSA) strains. The depsipeptide fijimycin A was found to contain eight subunits including α-phenylsarcosine (l-PhSar), N,β-dimethylleucine (l-DiMeLeu), Mar. Drugs 2020, 18, 329 20 of 43 sarcosine (Sar), 4-hydroxyproline (d-Hyp), and 3-hydroxypicolinic acid (3HyPic). Fijimycin A was defined as a stereoisomer of etamycin A containing d-α-phenylsarcosine. While comparing the structure of fijimycin B with fijimycin A, there was disappearance of α-phenylsarcosine (PhSar) and the existence of an N-methylleucine (l-NMeLeu) residue. Comparison of structures of fijimycins C and A suggested that the alanine (Ala) moiety in fijimycin A was replaced by a serine (Ser) unit. Etamycin A, also called virifogrisein I, was isolated from cultures of a terrestrial Streptomyces species which exhibited considerable activity against Gram-positive bacteria as well as Mycobacterium tuberculosis. Fijimycins A and C and etamycin A exhibited strong antibiotic activities against the three MRSA strains (ATCC33591, Sanger 252, UAMS1182). However, fijimycin B showed weak inhibition against both ATCC33591 and UAMS1182, which indicated that the α-phenylsarcosine unit might be vital for significant antibacterial activity. The similar antimicrobial activities of the stereoisomers fijimycin A and etamycin A suggested that substituting d- for l-α-phenylsarcosine had little effect on the anti-MRSA activities [126]. Jaspamide P is a sponge-derived modified jaspamide derivative possessing antimicrofilament activity and characterised by a modification of the N-methylabrine (N-methyl-2-bromotrypthophan) residue. Structural analysis of this cyclopeptide indicated the presence of a 4-methoxy-1,3-benzoxazine- 2-one heteroaromatic system. Jaspamide P was found to exhibit cytotoxic activity against HT-29 and MCF-7 tumour cell lines. Modifications of the methylabrine residue, claimed as essential for the observed biological activity, appeared to have little influence on the observed antiproliferative effect [127]. Wainunuamide is an unusual histidine containing cycloheptapeptide, containing three proline units. There were adjacent cis and trans proline residues in the structure of wainunuamide. Similar patterns were also found in cyclooligopeptide phakellistatin 8 and were found to be powerful β-turn inducers. The stereochemistry of all residues including histidine, phenylalanine, and leucine was found to be l. Wainunuamide exhibited weak cytotoxic activity in A2780 ovarian tumor and K562 leukemia cancer cells [128]. Ohmyungsamycins A and B are marine bacterium-derived cytotoxic and antimicrobial cyclic depsipeptides composed of 12 amino acid residues, including unusual amino acids such as N-methyl-4-methoxy-l-tryptophan, β-hydroxy-l-phenylalanine, and N,N-dimethylvaline. Ohmyungsamycins A and B showed significant inhibitory activities against diverse cancer cells as well as antibacterial effects against both Gram-positive and Gram-negative bacteria. Sungsanpin is a serine-rich lasso peptide containing 15 amino acid units from a deep-sea streptomycete in which eight amino acids form a cyclic peptide and the remaining seven amino acids including l-tryptophan unit form a tail that loops through the ring. It is the first example of a lasso peptide from a marine-derived microorganism and displays inhibitory activity with the human lung cancer cell line A549 in a cell invasion assay [129]. Desotamide and destolamide B are l-tryptophan containing bioactive peptides from marine microbe Streptomyces scopuliridis SCSIO ZJ46. These cyclohexapeptides displayed good antibacterial activities against Streptococcus pnuemoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus epidermidis (MRSE). In a complementary fashion, the antibacterial activities of destolamides revealed the “Tryptophan” moiety to be essential, thereby highlighting a critical structural element to this advancing antibacterial scaffold [130].

well as antibacterial effects against both Gram-positive and Gram-negative bacteria. Sungsanpin is a serine-rich lasso peptide containing 15 amino acid units from a deep-sea streptomycete in which eight amino acids form a cyclic peptide and the remaining seven amino acids including L-tryptophan unit form a tail that loops through the ring. It is the first example of a lasso peptide from a marine-derived microorganism and displays inhibitory activity with the human lung cancer cell line A549 in a cell invasion assay [129]. Desotamide and destolamide B are L-tryptophan containing bioactive peptides from marine microbe Streptomyces scopuliridis SCSIO ZJ46. These cyclohexapeptides displayed good antibacterial activities against Streptococcus pnuemoniae, Staphylococcus aureus, and methicillin-resistant Staphylococcus epidermidis (MRSE). In a complementary fashion, the antibacterial activities of destolamides revealed the “Tryptophan” moiety to be essential, thereby highlighting a critical structural element to this advancing antibacterial scaffold [130].

3. Stereochemical Aspects Stereochemistry includes the study of the relative arrangement of atoms or groups in a molecule in three-dimensional space and its understanding is crucial for the study of complex Mar. Drugsmolecules2020, 18, 329like heterocyclic peptides, which are of paramount biological significance. 21 of 43 cis,cis- and trans,trans-ceratospongamides (44,45) are new bioactive thiazole-containing cyclic heptapeptides from the marine red alga Ceratodictyon spongiosum and symbiotic sponge Sigmadocia one (l-isoleucine)-symbiotica. Thel-methyloxazoline structures of ceratospongamides residue, one l (-proline44,45) contained residue, two and L-phenylalanine one (l-proline)thiazole residues, one residue and were(L- foundisoleucine) to be-L-methyloxazoline proline amide residue, conformers. one L-proline The change residue, in and conformation one (L-proline)thiazole of a cyclooligopeptide residue ceratospongamideand were found from to “betrans proline” to amide “cis” resultedconformers in. The complete change lossin conformation of bioactivity, of a e.g.,cyclotrans,oligopeptide trans-isomer of ceratospongamideceratospongamide (45 from) was “ foundtrans” to to “ becis” a potentresulted inhibitorin complete of theloss expression of bioactivity of, ae.g. key, trans, enzyme in trans-isomer of ceratospongamide (45) was found to be a potent inhibitor of the expression of a key the inﬂammatory cascade, secreted phospholipase A2 (sPLA2), with an ED50 of 32 nM in a cell-based enzyme in the inflammatory cascade, secreted phospholipase A2 (sPLA2), with an ED50 of 32 nM in a model forcell anti-inﬂammation,-based model for anti- whereasinflammationcis,cis, whereas-isomer cis,cis (44-)isomer was inactive (44) was inactive [77] (Figure [77] (Fig 15ure). 15).

S O S 4 O cis-Pro trans-Pro4 N N N N N H 47 N O 24 H O * * O * 24 cis-Pro7 * 7 N O 47 N trans-Pro NH NH N H N H N N O O O O O O

44 45

Figure 15.FigureStructures 15. Structures of cis,cis of cis,cis-ceratospongamide-ceratospongamide ((4444) and trans,transtrans,trans-ceratospon-ceratospongamidegamide (45) with (45 ) with Pro-Tzl residuesPro-Tzl residues (*change (*change in stereochemistry in stereochemistry at at C-24 C-24 andand C C-47-47 carbonyls) carbonyls)..

UlithiacyclamidesUlithiacyclamides are thiazole-containing are thiazole-containing cyclopolypeptides, cyclopolypeptides, isolated isola fromted from the ascidian the ascidianLissoclinum Lissoclinum patella. Bicyclic isomeric ulithiacyclamides F and G contained one oxazoline and one patella. Bicyclic“free” threonine isomeric and ulithiacyclamides were found to be Fanhydro and G forms contained of ulithiacyclamide one oxazoline E. andUlithiacyclamides one “free” threonine F and wereand found G exhibited to be anhydro anti-multiple forms drug of ulithiacyclamide resistant (MDR) E.activity Ulithiacyclamides against vinblastine F and-resistant G exhibited anti-multipleCCRF- drugCEM human resistant leukemic (MDR) lymphoblasts activity against [51]. vinblastine-resistant CCRF-CEM human leukemic lymphoblastsLissoclinamides [51]. 4, 5, 7, and 8 are all cyclic heptapeptides derived from sea squirt Lissoclinum Lissoclinamidespatella that have 4, the 5, same 7, and sequence 8 are all of cyclic amino heptapeptides acids around the derived ring and from differ sea from squirt one anotherLissoclinum only patella in their stereochemistry or the number of thiazole and thiazoline rings. For lissoclinamide 8, the that have the same sequence of amino acids around the ring and differ from one another only in their valine residue was at position 31, the same sequence that occurs in lissoclinamide 4. Therefore, the stereochemistryonly difference or the between number lissoclinamides of thiazole and 4 and thiazoline 8 resided rings. in the Forstereochemistry lissoclinamide of one 8, orthe two valine of theresidue was at positionamino acids. 31, The the D same configuration sequence was that assigned occurs to in“Phe lissoclinamide-Tzl” and the L-configuration 4. Therefore, was the assigned only di toff erence d between lissoclinamides 4 and 8 resided in the stereochemistry of one or two of the amino acids. The configuration was assigned to “Phe-Tzl” and the l-configuration was assigned to “Val-Tzn” moiety in lissoclinamide 4. However, both lissoclinamides 4 and 8 contained similar residues like l-Pro-mOzn and l-Phe. Further, there was similarity in the structural components of lissoclinamides 2 and 3; the only difference was in the stereochemistry around Ala-Tzl moiety, d in the case of the former and l in the latter [55,56]. Lyngbyabellins are thiazole-containing halogenated peptolides derived from cyanobacteria, possessing cytotoxic properties. The configurations at C-15 and C-16 in lyngbyabellin A were found to be 15S and 16S. Further, C-26 and C-3 in the peptolide has the S configuration. The stereochemical assignments of lyngbyabellins E and H were found to be 2S, 3S, 14R, 20S, 26R, and 27S. The stereoconfigurations assigned to lyngbyabellin N was 2S, 3S, 14R, and 20S. The absolute configuration of the N,N-dimethylvaline (DiMeVal) residue in lyngbyabellin N was found to be l, whereas the absolute configurations of the leucine statine were determined to be 3R and 4S. The absolute configurations of lyngbyabellin J were found to be 2S, 3S, 14R, 20R, 21S, 27R, and 28S. An overall cyclic constitution was not required for potent cytotoxic properties in lyngbyabellins as acyclic peptides like lyngbyabellins F and I also exhibited significant cytotoxic properties [27–30]. The cyclopolypeptides bistratamides M and N (46,47) were found to be isomers of each other and differed in the configuration of alanine residue attached to the thiazole ring. The configuration was l in bistratamide M (46) and was found to be d in bistratamide N (47). Bistratamide M (46) was found to be slightly more cytotoxic against lung, breast, and pancreatic carcinoma cells in comparison to bistratamide N (47). Similarly, bistratamides K and L (50,51) are isomers, differing in the configuration of alanine residue attached to the thiazole ring. The configuration was d in bistratamide K (50) and Mar. Drugs 2020, 18, 21 of 42

“Val-Tzn” moiety in lissoclinamide 4. However, both lissoclinamides 4 and 8 contained similar residues like L-Pro-mOzn and L-Phe. Further, there was similarity in the structural components of lissoclinamides 2 and 3; the only difference was in the stereochemistry around Ala-Tzl moiety, D in the case of the former and L in the latter [55,56]. Lyngbyabellins are thiazole-containing halogenated peptolides derived from cyanobacteria, possessing cytotoxic properties. The configurations at C-15 and C-16 in lyngbyabellin A were found to be 15S and 16S. Further, C-26 and C-3 in the peptolide has the S configuration. The stereochemical assignments of lyngbyabellins E and H were found to be 2S, 3S, 14R, 20S, 26R, and 27S. The stereoconfigurations assigned to lyngbyabellin N was 2S, 3S, 14R, and 20S. The absolute configuration of the N,N-dimethylvaline (DiMeVal) residue in lyngbyabellin N was found to be L, whereas the absolute configurations of the leucine statine were determined to be 3R and 4S. The absolute configurations of lyngbyabellin J were found to be 2S, 3S, 14R, 20R, 21S, 27R, and 28S. An overall cyclic constitution was not required for potent cytotoxic properties in lyngbyabellins as acyclic peptides like lyngbyabellins F and I also exhibited significant cytotoxic properties [27–30]. The cyclopolypeptides bistratamides M and N (46,47) were found to be isomers of each other and differed in the configuration of alanine residue attached to the thiazole ring. The configuration was L in bistratamide M (46) and was found to be D in bistratamide N (47). Bistratamide M (46) was Mar. Drugsfound2020 , to18 , 329be slightly more cytotoxic against lung, breast, and pancreatic carcinoma cells in 22 of 43 comparison to bistratamide N (47). Similarly, bistratamides K and L (50,51) are isomers, differing in the configuration of alanine residue attached to the thiazole ring. The configuration was D in was foundbistratamide to be l inK ( bistratamide50) and was found L (51 to). be Further, L in bistratamide bistratamide L (51). G Further, (39) was bistratamide found to G be (39O) -isosterewas of bistratamidefound Hto (40be )O and-isostere bistratamide of bistratamide J was foundH (40) toand be bistratamideS-isostere of J bistratamidewas found to Ibe (41 S).-isostere The compounds of containingbistratamide two thiazole I (41). The rings compounds were found containing to be moretwo thiazole active ri thanngs were those found containing to be more a thiazoleactive than ring and an oxazolethose ring containing [50,61 ].a Moreover,thiazole ring the and gross an oxazole structure ring of [50,61]. cytotoxic Moreover, cyclopeptide the gross keramamide structure of G (49) was foundcytotoxic to be cyclopeptide almost the keramamide same as that G (49 of) was keramamide found to be Falmost (48), the the sa onlyme as change that of keramamide being the diF ﬀerent (48), the only change being the different stereochemistry at C-13 of the α-keto-β-amino acid (Figure α β stereochemistry16). at C-13 of the -keto- -amino acid (Figure 16).

O O O O H H O S N * N 26 * H N N N N N 20 S H 13 H H * H N H HO O O O O N NH O O N O N O HN O NH O N NH HN N N N O NH H O S S S O N H 46: *20L 47: *20D 48: *13R 49: *13S 50: 26D 51: *26L

Figure 16.FigureStructures 16. Structures of bistratamide of bistratamide M M ( 46(46)) withwith configuration configuration L atl C-20,at C-20, bistratamide bistratamide N (47) Nwith (47 ) with configuration D at C-20, keramamide F (48) with stereochemistry R at C-13, keramamide G (49) with configuration d at C-20, keramamide F (48) with stereochemistry R at C-13, keramamide G (49) with stereochemistry S at C-13, bistratamide K (50) with configuration D at C-26, and bistratamide L (51) stereochemistry S at C-13, bistratamide K (50) with configuration d at C-26, and bistratamide l (51) with configuration L at C-26. with configuration l at C-26. Grassypeptolides D and E are diasteromeric cyclic peptides from a red sea Leptolyngbya Grassypeptolidescyanobacterium. These D and cyclodepsipeptides E are diasteromeric were found cyclic to peptides contain fromtwo aromatic a redsea residues,Leptolyngbya cyanobacterium.phenyllactic These acid cyclodepsipeptides (Pla), N-methylphenylalanine were found to( containN-Me-Phe); two aromaticβ-amino residues,acid residue phenyllactic acid (Pla),2-methyl-3-aminobutyricN-methylphenylalanine acid (Maba); (N-Me-Phe); and 2-aminobutyricβ-amino acid acid residue (Aba) residue. 2-methyl-3-aminobutyric Further, structural acid analysis indicated the presence of a 2-methylthiazoline carboxylic acid derived from (Maba); and 2-aminobutyric acid (Aba) residue. Further, structural analysis indicated the presence of N-methylphenylalanine (N-Me-Phe-4-Me-thn-ca) and an Aba-thn-ca unit. Grassypeptolides D and E a 2-methylthiazoline carboxylic acid derived from N-methylphenylalanine (N-Me-Phe-4-Me-thn-ca) showed significant cytotoxicity to HeLa (IC50: 335 and 192 nM) and mouse neuro-2a blastoma cells and an Aba-thn-ca(IC50: 599 and unit. 407 Grassypeptolides nM). These depsipeptides D and E showedwere found significant to be threonine/N-methylleucine cytotoxicity to HeLa (IC 50: 335 and 192 nM) and mouse neuro-2a blastoma cells (IC50: 599 and 407 nM). These depsipeptides were found to Ma ber. Drugs threonine 2020, 18, /N-methylleucine diastereomers and possesssed different configurations22 of 42 for both l l -Thr anddiastereomersN-Me- -Leu and in grassypeptolide possesssed different E ( 53 configurations) relative to grassypeptolide for both L-Thr D and (52 N).-MeGrassypeptolide-L-Leu in D (7R,11Rgrassypeptolide; d-allo-Thr and E (53N)-Me- relatived-Leu) to grassypeptolide (52) was found D (52 to). Grassypeptolide be approximately D (7R 1.5-fold,11R; D-allo less-Thr cytotoxic and to HeLa cervicalN-Me-D carcinoma-Leu) (52) was and found neuro-2a to be approximately mouse blastoma 1.5-fold cells less than cytotoxic grassypeptolide to HeLa cervical E (7 carcinomaS,11S; l-Thr and N-Me-lan-Leu)d neuro (53).-2a Moreover, mouse blastoma grassypeptolides cells than grassypeptolide A and C were E (7 foundS,11S; toL-Thr be the and NN-methylphenylalanine-Me-L-Leu) (53). epimersMoreover, with stereochemistry grassypeptolides (7R A,11 andR,25 C R were,29R found) and (7to R be,11 theR,25 N-Rmethylphenylalanine,29S), respectively. epimers Grassypeptolide with C stereochemistry (7R,11R,25R,29R) and (7R,11R,25R,29S), respectively. Grassypeptolide C showed showed 16–23-fold greater potency than grassypeptolide A against colorectal adenocarcinoma HT29 16–23-fold greater potency than grassypeptolide A against colorectal adenocarcinoma HT29 and and cervicalcervical carcinoma carcinoma HeLaHeLa cells cells [25 [25] (Figure] (Figure 17) .17 ).

N N N N N N O O O O O O O O O O N N S S

HN HN O O O O NH NH 7 * 7 O O * O O N N N N OH 11 OH H 11 H N S * N S *

52: *7R,11R 53: *7S,11S

Figure 17.FigureStructures 17. Structures of grassypeptolide of grassypeptolide D D ( 52(52)) withwith stereochemistr stereochemistryy R atR Cat-7 and C-7 C and-11 of C-11 D-allo of-Thrd-allo -Thr and N-Me-and dN-Leu-Me-D residues-Leu residues and and grassypeptolide grassypeptolide EE ((53)) with with stereochemistry stereochemistry S at CS-at7 and C-7 C and-11 of C-11 L-Thr of l-Thr and N-Me-L-Leu residues. and N-Me-l-Leu residues. Nostocyclamide M (54) and tenuecyclamide C (55) were found to be diasteromers. Nostocyclamide M (54) has the same constitution as tenuecyclamide C (55) but differs in the configuration of methionine in the structure. Adjacent to one of thiazole ring, D-methionine was present in cyclic hexapeptide nostocyclamide M (54) wheresas there was L-methionine in cyclic hexapeptide tenuecyclamide C (55). Nostocyclamide M (54) displayed allelopathic activity like nostocyclamide but was inactive against grazers unlike the latter [36] (Figure 18).

O O

S S N N H H N N O N O N

HN O HN O NH NH N * N * 12 S 12 S O S O S 54: *12D 55: *12L

Figure 18. Structures of nostocyclamide M (54) with Gly-Tzl and Met-Tzl residues, having methionine configuration D at C-12, and tenuecyclamide C (55) with Gly-Tzl and Met-Tzl residues, having methionine configuration L at C-12.

Ulongamides (1–3) are thiazole-containing cytotoxic cyclic depsipeptides with a novel β-amino acid, 3-amino-2-methylhexanoic acid (Amha), stereochemistry which differentiates ulongamides A–C from ulongamides D–F. The former has the Amha residue in 2R,3R configuration, while the latter contains an Amha unit in 2S,3R configuration. The 2-hydroxy-3-methylpentanoic acid (Hmpa) residue was found to be part of ulongamide E and F (3) structures, and the configuration of the residue was 2S,3S. Furthermore, stereochemistry of the 2-hdroxyisovaleric acid (Hiva) unit present in ulongamide D (2) was found to be S [13].

Mar. Drugs 2020, 18, 22 of 42

diastereomers and possesssed different configurations for both L-Thr and N-Me-L-Leu in grassypeptolide E (53) relative to grassypeptolide D (52). Grassypeptolide D (7R,11R; D-allo-Thr and N-Me-D-Leu) (52) was found to be approximately 1.5-fold less cytotoxic to HeLa cervical carcinoma and neuro-2a mouse blastoma cells than grassypeptolide E (7S,11S; L-Thr and N-Me-L-Leu) (53). Moreover, grassypeptolides A and C were found to be the N-methylphenylalanine epimers with stereochemistry (7R,11R,25R,29R) and (7R,11R,25R,29S), respectively. Grassypeptolide C showed 16–23-fold greater potency than grassypeptolide A against colorectal adenocarcinoma HT29 and cervical carcinoma HeLa cells [25] (Figure 17).

N N N N N N O O O O O O O O O O N N S S

HN HN O O O O NH NH 7 * 7 O O * O O N N N N OH 11 OH H 11 H N S * N S *

52: *7R,11R 53: *7S,11S Mar. Drugs 2020, 18, 329 23 of 43 Figure 17. Structures of grassypeptolide D (52) with stereochemistry R at C-7 and C-11 of D-allo-Thr and N-Me-D-Leu residues and grassypeptolide E (53) with stereochemistry S at C-7 and C-11 of L-Thr and N-Me-L-Leu residues. Nostocyclamide M (54) and tenuecyclamide C (55) were found to be diasteromers. Nostocyclamide M(54) has theNostocyclamide same constitution M (54 as) tenuecyclamideand tenuecyclamide C (55 C) but(55) di wereﬀers in found the conﬁguration to be diasteromers. of methionine in the structure.Nostocyclamide Adjacent M (54 to) has one the of same thiazole constitution ring, d -methionine as tenuecyclamide was presentC (55) but in differs cyclic in hexapeptide the nostocyclamideconfiguration M ( 54 of ) methionine wheresas inthere the was structure.l-methionine Adjacent to in one cyclic of thiazole hexapeptide ring, D tenuecyclamide-methionine was C (55). present in cyclic hexapeptide nostocyclamide M (54) wheresas there was L-methionine in cyclic Nostocyclamide M (54) displayed allelopathic activity like nostocyclamide but was inactive against hexapeptide tenuecyclamide C (55). Nostocyclamide M (54) displayed allelopathic activity like grazersnostocyclamide unlike the latter but [was36] inactive (Figure against 18). grazers unlike the latter [36] (Figure 18).

O O

S S N N H H N N O N O N

HN O HN O NH NH N * N * 12 S 12 S O S O S 54: *12D 55: *12L FigureFigure 18. Structures 18. Structures of ofnostocyclamide nostocyclamide M ( (5454) )w withith Gly Gly-Tzl-Tzl and and Met- Met-TzlTzl residues, residues, having having methioninemethionine configuration configurationd at D C-12,at C-12 and, and tenuecyclamide tenuecyclamide C C(55 (55) with) with Gly- Gly-TzlTzl and Met and-Tzl Met-Tzl residues, residues, having methioninehaving methionine configuration configurationl at L at C-12. C-12. Ulongamides (1–3) are thiazole-containing cytotoxic cyclic depsipeptides with a novel β-amino Ulongamides (1–3) are thiazole-containing cytotoxic cyclic depsipeptides with a novel β-amino acid, 3-amino-2-methylhexanoic acid (Amha), stereochemistry which differentiates ulongamides acid, 3-amino-2-methylhexanoicA–C from ulongamides D–F. acid The (Amha),former ha stereochemistrys the Amha residue which in 2R,3 diRff configuration,erentiates ulongamides while the A–C from ulongamideslatter contains D–F.an Amha The unit former in 2S,3 hasR configuration. the Amha residueThe 2-hydroxy in 2R-3,3-methylpentanoicR configuration, acid while (Hmpa) the latter containsresidue an Amha was unitfound in to 2 S be,3 R partconfiguration. of ulongamide The E and 2-hydroxy-3-methylpentanoic F (3) structures, and the configuration acid (Hmpa) of the residue was foundresidue to bewas part 2S,3 ofS. ulongamideFurthermore, stereochemistry E and F (3) structures, of the 2-hdroxyisovaleric and the configuration acid (Hiva) ofunit the present residue was in ulongamide D (2) was found to be S [13]. 2MaS,3r. SDrugs. Furthermore, 2020, 18, stereochemistry of the 2-hdroxyisovaleric acid (Hiva) unit present in ulongamide23 of 42 d (2) was found to be S [13]. CalyxamidesCalyxamides A and B B ((5656,,5757)) areare cyclic cyclic peptides peptides containing containing 5-hydroxytryptophan 5-hydroxytryptophan (Htrp),(Htrp), isolatedisolated from from the the marine marine sponge sponge DiscodermiaDiscodermia calyx calyx.. TheseThese peptides peptides contained contained residues residues like like 2,3-diaminopropionic2,3-diaminopropionic acidacid (Dpr) (Dpr) in in addition addition to to (O (O-methylseryl)thiazole-methylseryl)thiazole moiety. moiety.Calyxamides Calyxamides A A and and B (B56 ,(5756),57 possessed) possessed the the same same planar planar structure structure but but are are isomeric isomeric at at thethe 3-position3-position of of the the 3-amino-2-keto-4-methylhexanoic3-amino-2-keto-4-methylhexanoic acid (AKMH) residue residue like like keramamides keramamides F F and and G G (13 (13SS andand 13 R)).. StructuresStructures of of calyxamides calyxamides di difffferer in in stereochemistry stereochemistry on on isoleucine isoleucine moiety moiety adjacent adjacent to to ((OO-methylseryl)thiazole-methylseryl)thiazole moiety. moiety. Calyxamide Calyxamide B B ( 57(57) was) was found found to to be be the the diastereomer diastereomer of of calyxamide calyxamide A (A56 ()56 and) and displayed displayed more more cytotoxicity cytotoxicity against against P388 P388 murine murine leukemia leukemia cells, cells, with with an IC an50 valueIC50 value of 0.9 ofµ 0.9M, inμM, comparison in comparison to calyxamide to calyxamide A (IC A50 :(IC 3.950:µ 3.9M) μM (56)[) (11056) ][110 (Figure] (Figure 19). 19).

H H O N H O H O H H N N O H H O H N O N N H O O H NH N H N N 2 O Y NH H N H NH X H O Y O NH X 2 O H N O O H H O O O O N NH HN NH NH N HO O N O

HO S S O O

56: X = Y = S 57: X = Y = R

FigureFigure 19.19. StructuresStructures ofof calyxamide calyxamide A A (56 (56) with) withO -Me-Ser-TzlO-Me-Ser-Tzl moiety, moiety having, having stereochemistry stereochemistryS at S the at 3-positionthe 3-position of 3-amino-2-keto-4-methylhexanoic of 3-amino-2-keto-4-methylhexanoic acid acid (AKMH) (AKMH residue,) residue and, Calyxamideand Calyxamide B (57 )B with (57) Owith-Me-Ser-Tzl O-Me-Ser moiety,-Tzl moiety, having having stereochemistry stereochemistryR at the R 3-positionat the 3-position of AKMH of AKMH residue. residue.

Aciculitamides A and B are bicyclic E and Z isomeric peptides obtained from the lithistid sponge Aciculites orientalis and result from oxidation of the imidazole ring of aciculitins A–C, bicycles containing an unusual histidino-tyrosine bridge. Aciculitamide A did not show any cytotoxicity against HCT-116 and/or antifungal activity [118]. Sclerotides A and B are cyclopolypeptides from marine-derived fungus, Aspergillus sclerotiorum PT06-1. These cyclic hexapeptides contained amino acid residues like L-threonine, L-alanine, phenylalanine, serine, anthranilic acid (AA), and dehydrotryptophan (∆-Trp). Sclerotides A and B were found to be Z and E isomers and differed in stereochemistry of dehydrotryptophan. Sclerotide B showed more antifungal activity against Candida albicans with MIC values of 3.5 µM in comparison to sclerotide A (MIC: 7 µM). In addition, sclerotide B exhibited weak cytotoxic activity against the HL-60 cell line (IC50: 56.1 µM) and selective antibacterial activity against Pseudomonas aeruginosa (MIC: 35.3 µM) [131].

Mar. Drugs 2020, 18, 329 24 of 43

Aciculitamides A and B are bicyclic E and Z isomeric peptides obtained from the lithistid sponge Aciculites orientalis and result from oxidation of the imidazole ring of aciculitins A–C, bicycles containing an unusual histidino-tyrosine bridge. Aciculitamide A did not show any cytotoxicity against HCT-116 and/or antifungal activity [118]. Sclerotides A and B are cyclopolypeptides from marine-derived fungus, Aspergillus sclerotiorum PT06-1. These cyclic hexapeptides contained amino acid residues like l-threonine, l-alanine, phenylalanine, serine, anthranilic acid (AA), and dehydrotryptophan (∆-Trp). Sclerotides A and B were found to be Z and E isomers and diﬀered in stereochemistry of dehydrotryptophan. Sclerotide B showed more antifungal activity against Candida albicans with MIC values of 3.5 µM in comparison to sclerotide A (MIC: 7 µM). In addition, sclerotide B exhibited weak cytotoxic activity against the HL-60 cell line (IC50: 56.1 µM) and selective antibacterial activity against Pseudomonas aeruginosa (MIC: 35.3 µM) [131].

4. Synthesis of Heterocyclic Peptides Despite of lot of challenges associated with synthesizing complex peptide molecules [132–135], syntheses of diverse aromatic/heteroaromatic peptides were accomplished by several research groups employing diverse techniques of peptide synthesis including solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), and a mixed solid-phase/solution synthesis strategy, irrespective of whether these congeners belong to linear analogues [136–151] or are cyclic in nature [152–169]. Literature is enriched with reports involving synthesis of various heterocyclic cyclopolypeptides bearing thiazole/thiazoline/tryptophan/histidine moieties viz. cyclodidemnamide B[42], dolastatin 3 [90], aeruginazole A [170], didmolamide B (29)[171], dolastatin 10 (20)[172], scleritodermin A (10)[173], obyanamide (8)[174,175], marthiapeptide A [176], diandrine C [177], diandrine A [178], sarcodactylamide [179], segetalin C [180], segetalin E [181], annomuricatin B [182], and gypsin D [183]. The first total synthesis of thiazole and methyloxazoline-containing cyclohexapeptides didmolamides A and B was accomplished by the solid phase assembly of thiazole-containing amino acids and Fmoc-protected α-amino acids. The synthesis of thiazole-containing didmolamide B(29) was also achieved using solution phase peptide synthesis. The crucial thiazole amino acid was synthesized by MnO2 oxidation of a thiazoline prepared from an Ala-Cys dipeptide using bis(triphenyl)oxodiphosphonium trifluoromethanesulfonate. The final macrolactamization was accomplished efficiently by benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoro- phosphate (PyBOP) and 4-dimethylaminopyridine (DMAP) [171]. A practical approach to asymmetric synthesis of dolastatin 10 (20) was found to involve SmI2-induced cross-coupling and asymmetric addition of chiral N-sulfinyl imine [172]. The synthesis of the C1–N15 fragment of the marine natural product scleritodermin A (10) was accomplished through a short and stereocontrolled sequence. The highlights of this route included synthesis of a novel conjugated thiazole moiety 2-(1-amino-2-p-hydroxyphenylethane)-4- (4-carboxy-2,4-dimethyl-2Z,4E-propadiene)-thiazole (ACT) fragment and the formation of the α-keto amide linkage by the use of a highly activated α,β-ketonitrile [173]. The total synthesis of a cytotoxic N-methylated thiazole-containing cyclic depsipeptide obyanamide (8) was accomplished that included the preparation of two protected fragments before macrocyclization, starting from material (S)-2-aminobutyric acid. The synthesis has led to a reassignment of the C-3 configuration in β-amino acid residue. As a result, the configuration at C-3 position has been amended as R [174,175]. The cytotoxic polythiazole-containing cyclopeptide marthiapeptide A having a linked trithiazole thiazoline system was synthesized via two routes. The initial strategy involved − a macrocyclization of the linear precursor via a peptide-coupling reaction between the amine on the alanine residue and the carboxylic acid end of isoleucine. However, the cyclization was not successful, which was attributed to the closing point being too close to the rigid heterocyclic thiazole moiety. The second strategy involved closing between the thiazoline and peptide in which successful Mar. Drugs 2020, 18, 329 25 of 43 cyclization can be attributed to the flexibility of the thiazoline, which allows a connection between the molecule’s head and tail [176].

5. Structural Activity Relationships Structural activity relationships (SAR) are prime keys to diverse aspects of drug discovery, ranging from primary screening to extensive lead optimization. SAR can be used to predict bioactivity from the molecular structure. This powerful technology is used in drug discovery to guide the acquisition or synthesis of desirable new compounds as well as to further characterize existing molecules. The principle of structure–activity relationship indicated that there is a relationship between molecular structures and their biological activity and solely depends on the recognition of which structural characteristics correlate with chemical and biological reactivity. The lissoclinamides, heterocyclic peptides isolated from sea squirt Lissoclinum patella, are derived from a cyclic heptapeptide in which a threonine has been cyclised to an oxazoline and two cysteines have been cyclised to give a thiazole or thiazoline. While comparing natural and synthetic lissoclinamides, it was found that the replacement of thiazoline rings with oxazolines decreased activity to a greater extent than replacement of oxazoline rings with thiazolines [184]. This study further showed that it was not the individual components of the macrocycle that conferred high activity, but rather, the overall conformation of this molecule was responsible for the bioactivity. While comparing structures of lissoclinamides 4 and 5, it was observed that these compounds differ only in the oxidation state of a single thiazole unit but that this difference makes lissoclinamide 5 two orders of magnitude less cytotoxic than lissoclinamide 4 against bladder carcinoma (T24) cells [55]. In raocyclamides (42,43), the presence of oxazoline moiety was found to be essential for cytotoxicity against sea urchin embryos. The cyanobacterium-derived cyclopolypeptides raocyclamide A and B (42,43) possessed thiazole and oxazoline rings in their composition, but raocyclamide A (42) contained an additional oxazoline moiety in its structure. This structural change results in a lot of variation in the biological response. While comparing the bioeffects of these cyclopolypeptides, it was found that raocyclamide A (42) inhibited the division of embryos of Paracentrotus lividus with an effective dose for 100% inhibition (ED100) of 30 µg/mL, whereas raocyclamide B (43) was inactive even at the concentrations of 250 µg/mL [32]. Replacement of d-valine moiety with d-methionine adjacent to one of the thiazole rings in the structure of macrocyclic thiazole and methyloxazole-containing allelochemical nostocyclamide resulted in cyanobacterial cyclopeptide nostocyclamide M (54) with inactivity toward grazers, but this structural modification does not affect the allelopathic activity against anabaena 7120 [36]. The reduction of isoleucylthiazole (Ile-Tzl) residue of a thiazole- and methyloxazoline-containing cyclooligopeptide of cyanobacterial origin, aerucyclamide B, to an isoleucylthiazoline (Ile-Tzn) residue resulted in a close analogue aerucyclamide A. From this one structural modification, the antiplasmodial activity was found to decrease by 1 order of magnitude. Further, the cyclohexapeptide aerucyclamide C underwent hydrolysis reaction using trifluoroacetic acid to form ring-opened products microcyclamide 7806A and microcyclamide 7806B. This change in structure from rigid, disk-like cyclamides to methyloxazoline (mOzn) ring-opened hydrolysis products resulted in loss of antimicrobial and cytotoxic activities [38]. In comparison, aerucyclamide B was the most active antiplasmodial compound among aerucyclamides against chloroquine-resistant strain K1 of P. falciparum, with selectivity against a rat myoblast cell line, whereas against parasite T. brucei rhodesiense, the most active compound was aerucyclamide C. The cyclic structure of oxazole-rich, thiazole-containing polypeptide mechercharmycin A was found to be essential for its strong antitumor activity against human lung cancer and leukemia cells. The cyclic ring opening of mechercharmycin A resulted in linear peptide mechercharmycin B which did not displayed any inhibitory activity toward any of the cell lines [79]. The ascidian-derived cytotoxic cyclic hexapeptides, bistratamides A and B, differed from each other only by the presence or absence of one double bond. The conversion of one thiazoline in Mar. Drugs 2020, 18, 329 26 of 43 bistratamide A to a thiazole in bistratamide B, i.e., oxidation of thiazoline to thiazole, resulted in a less toxic compound. For example, comparing bioactivities of bistratamides A and B, the former has an IC50 value of about 50 µg/mL and latter has an IC50 value greater than 100 µg/mL against human cell lines including fibroblasts and bladder carcinoma cells [60]. Replacement of the alanine unit adjacent to the thiazole ring by a threonine unit in cyanobacterium-derived modified cyclohexapeptide venturamide A (31) resulted in a related cyclic hexapeptide venturamide B (32). This structural change reflected an increase in antimalarial activity against Plasmodium falciparum and cytotoxic activity toward mammalian Vero cells. However, with this modification, a decrease in bioactivity against Trypanasoma cruzi and MCF-7 cancer cells was observed [34]. The lyngbyabellin family of thiazole-containing peptolides are known to exhibit moderate to potent cytotoxicity against a number of different cancer cell types through the promotion of actin polymerization. In the HCT116 colon cancer cell line assay, reproducible IC values (40.9 3.3 nM) 50 ± were obtained for lyngbyabellin N, confirming the potent cytotoxic effect of this new member of the lyngbyabellin class and suggesting that the side chain of lyngbyabellin N was an essential structural feature for this potent activity. However, this trend was not entirely consistent within this structure class as other lyngbyabellin analogs lacking the side chain were found to exhibit bioactivity against HT29 and HeLa cells [29]. When compared to lyngbyabellin A, lyngbyabellin J displayed slightly less bioactivity against HT29 colorectal adenocarcinoma and HeLa cervical carcinoma cells. The cytoskeletal actin-disrupting lyngbyabellin 27-deoxylyngbyabellin A was found to be more potent than lyngbyabellin A against HT29 and HeLa carcinoma cell lines (IC50 values: 27-deoxylyngbyabellin A, 0.012 and 0.0073 µM; lyngbyabellin A, 0.047 and 0.022 µM), indicating the importance of hydroxylation at the C-27 position. However, lyngbyabellin A, its 27-deoxy analog, and lyngbyabellin J exhibited more cytotoxic activity against the two cell lines when compared to peptolide lyngbyabellin B (IC50 values: 1.1 and 0.71 µM). The configuration of the hydroxy acid-derived unit esterified to the 7,7-dichloro-3-acyloxy-2-methyloctanoic acid residue (here, Dhmpa) was not found to have a profound effect on the activity. Furthermore, close analysis of bioactivity data indicated that the cytotoxicity of cyclic and acyclic lyngbyabellins appeared to be similar [30]. The antithrombin cyclopolypeptides and cyclotheonellazoles had structural features similar to another Theonella sponge-derived peptide oriamide (9) in having nonproteinogenic amino acids like 4-propenoyl-2-tyrosylthiazole and 3-amino-4-methyl-2-oxohexanoic acid and showed potent inhibitory activity against the serine protease enzymes chymotrypsin and elastase. Cyclotheonellazole complexes with elastase/chymotrypsin exhibit a tetrahedral transition state involving the keto group of Amoha and Ser195 of elastase, while the side chain of Amoha fits in the enzyme S1 pocket. Cyclotheonellazole A, which contains a 2-aminopentanoic acid residue, was found to be the most potent inhibitor. This was probably due to a better compatibility with the enzyme S2 subsite. Cyclotheonellazoles B and C contained the amino acids leucine and homoalanine, and it appeared that the length and the branching of the aliphatic chain influenced the bioactivity. Further, these cyclopeptides were inactive against the malaria parasite plasmodium falciparum at IC50 values of greater than 20 µg/mL [68]. Ulongamides (1–3) are cyanobacterium-derived β-amino acid- and thiazole-containing cyclic peptides with weak cytotoxic properties. In cyclodepsipeptide ulongamide F (3), the lack of an aromatic amino acid or the N-methyl group adjacent to the hydroxyl acid (N-methylphenylalanine/N-methyl tyrosine in ulongapeptides A–E and l-valine in ulongapeptide F) was found to be detrimental to bioactivity. This was evident from the observation that ulongamide F (3) was inactive at <10 µM against KB and LoVo cells in comparison to ulongapeptides A (1) and D (2), which displayed cytotoxicity against both cell lines [13].

6. Biological Activity Although thiazole-containing cyclopolypeptides of marine origin are associated with a number of bioactivities including antitubercular, antibacterial, antifungal, and inhibitory activity against serine Mar. Drugs 2020, 18, 329 27 of 43 protease enzymes chymotrypsin and elastase; anti-HIV activity; antiproliferative activity; antimalarial activity; and inhibitory activity against the transcription factor activator protein-1, the majority of them were found to exhibit anticancer activity. Various pharmacological activity-associated marine-derived Tzl-containing cyclopolypeptides along with susceptible cell line/organism with minimum inhibitory concentration are tabulated in Table2.

Table 2. Heterocyclic Tzl-based peptides (TBPs) with diverse pharmacological activities.

Bioactivity TBPs Resource Susceptibilty MICa Value Cytotoxicity against A-549 (lung), marine sponge 5.17–15.62 Haligramide A [63] HCT-15 (colon), SF-539 (CNSb), and SNB-19 Haliclona nigra µg/mL (CNS) human tumor cell lines Cytotoxicity against A-549 (lung), marine sponge Haligramide B [63] HCT-15 (colon), SF-539 (CNS), and SNB-19 3.89–8.82 µg/mL Haliclona nigra (CNS) human tumor cells marine sponge Cytotoxicity against colon HCT116, ovarian Scleritodermin A [64] 0.67–1.9 µM Scleritoderma nodosum A2780, and breast SKBR3 cell lines marine cyanobacterium Obyanamide [12] Cytotoxicity against KBc and LoVo cells 0.58 and 3.14 µg/mL Lyngbya confervoides marine sponge Anti-TB activity against Mycobacterium Waiakeamide [66] 7.8 µg/mL Ircinia dendroides tuberculosis marine cyanobacterium Ulongamide A [13] Cytotoxicity against KB and LoVo cells 1 and 5 µM Lyngbya sp. marine cyanobacterium Cytotoxicity against mouse neuroblastoma Guineamide B [14] 15 µM Lyngbya majuscula cell line marine sponge Cytotoxicity against P388 murine Calyxamide A [110] 3.9 and 0.9 µM Discodermia calyx leukemia cells marine ascidian Cytotoxic activity against the human colon Bistratamide J [50] 1.0 µg/mL Lissoclinum bistratum tumor (HCT-116) cell line Cytotoxicity against several Didmolamide A marine tunicate cultured tumor cell lines (A549, HT29, and 10–20 µg/mL and B [48] Didemnum molle MEL28) Antibacterial activity againt freshwater B. subtilis and S. albus 2.2 and 8.7 µM Aeruginazole A [91] cyanobacterium Cytotoxicity against MOLT-4 human 41 and 22.5 µM Microcystis sp. leukemia cell line and peripheral blood lymphocytes Inhibitory activity against serine protease 0.62, 2.8, and Cyclotheonellazole A, B marine sponge enzyme chymotrypsin 2.3 nM and C [68] Theonella aff. swinhoei Inhibitory activity against serine protease 0.034, 0.10, and 0.099 enzyme elastase nM Microcyclamide MZ602 cyanobacterium Inhibition activity of 75 µM [18] Microcystis sp. chymotrypsin Inhibition of HIV-1 integrase (for the marine cyanobacterium 5 mM Dolastatin 3 [9] terminal-cleavage and strand- Lyngbya majuscula and 4.1 mM transfer reactions) Cytotoxicity against KB cells (human nasopharyngeal carcinoma cell line) and LoVo cells (human colon adenocarcinoma cell line) 0.03 and 0.50 µg/mL marine cyanobacterium Lyngbyabellin A [27] Cytotoxicity against HT29 colorectal 1.1 and 0.71 µM Lyngbya majuscula adenocarcinoma and HeLa cervical 0.01–5.0 µg/mL carcinoma cells Cytoskeletal-disrupting effects in A-10 cells Toxicity to brine shrimp (Artemia salina) Antifungal activity against Candida albicans 3.0 ppm marine cyanobacterium (ATCC 14053) in a disk diffusion assay Lyngbyabellin B [86] 100 µg/disk Lyngbya majuscula Cytotoxicity against HT29 colorectal 1.1 and 0.71 µM adenocarcinoma and HeLa cervical carcinoma cells Cytotoxicity against NCI-H460 human lung Lyngbyabellin E [28] marine cyanobacterium tumor and neuro-2a mouse neuroblastoma 0.4 and 1.2 µM Lyngbya majuscula cells 0.01–6.0 µM Cytoskeletal-disrupting effects in A-10 cells Mar. Drugs 2020, 18, 329 28 of 43

Table 2. Cont.

Bioactivity TBPs Resource Susceptibilty MICa Value Cytotoxicity against NCI-H460 human lung marine cyanobacterium Lyngbyabellin H [28] tumor and neuro-2a mouse neuroblastoma 0.2 and 1.4 µM Lyngbya majuscula cells marine cyanobacterium Cytotoxic activity against HCT116 colon Lyngbyabellin N [29] 40.9 nM Moorea bouilloni cancer cell line Cytotoxicity against HT29 colorectal 27-Deoxy- marine cyanobacterium adenocarcinoma and HeLa cervical 0.012 and 0.0073 µM lyngbyabellin A [30] Lyngbya bouillonii carcinoma cells Cytotoxicity against HT29 colorectal marine cyanobacterium Lyngbyabellin J [30] adenocarcinoma and HeLa cervical 0.054 and 0.041 µM Lyngbya bouillonii carcinoma cells ﬁlamentous Cytotoxicity against embryos of sea urchin Raocyclamide A [32] cyanobacterium 30 µg/mL (ED )d Paracentrotus lividus 100 Oscillatoria raoi cultured cyanobacterium Tenuecyclamide A, C Cytotoxicity against embryos of sea urchin 10.8, 9.0, and 19.1 µM Nostoc spongiaeforme and D [105] Paracentrotus lividus (ED ) var. tenue 100 sea hare Dolastatin I [75] Cytotoxicity against HeLa S cells 12 µg/mL Dolabella auricularia 3 Antibacterial activities against Micrococcus luteus, Staphylococcus aureus, Bacillus subtilis, and Bacillus thuringiensis 2.0, 8.0, 4.0, and 2.0 marine actinomycete Cytotoxicity against SF-268 (human µg/mL Marinactinospora Marthiapeptide A [74] glioblastoma) cell line, MCF-7 (human 0.38, 0.43, 0.47, and thermotolerans SCSIO breast adenocarcinoma) cell line, NCI-H460 0.52 µM 00652 (human lung carcinoma) cell line, and HepG2 (human hepatocarcinoma) cancer cell line Cytotoxicity against L1210 murine Keramamide G, H marine sponge leukemia cells and KB human 10 µg/mL and J [67] Theonella sp. epidermoid carcinoma cells Cytotoxicity against L1210 murine marine sponge Keramamide K [109] leukemia cells and KB human 0.72 and 0.42 µg/mL Theonella sp. epidermoid carcinoma cells Cytotoxicity against T24 (bladder sea squirt Lissoclinamide 8 [55] carcinoma cells), MRC5CV1 (ﬁbroblasts), 6, 1, and 8 µg/mL Lissoclinum patella and lymphocytes marine bacterium Cytotoxic activity against A549 (human 4.0 10 8 M and 4.6 Mechercharmycin A [79] Thermoactinomyces sp. lung cancer) cells and Jurkat cells (human × − 10 8 M YM3-251 leukemia) × − marine sponge Cytotoxicity against HM02, HepG2, and Leucamide A [70] 5.2, 5.9, and 5.1 µg/mL Leucetta microraphis Huh7 tumor cell lines marine ascidian Cytotoxic activity against the human colon Bistratamide H [50] 1.7 µg/mL Lissoclinum bistratum tumor (HCT-116) cell line Cytotoxicity against human colon tumor marine ascidian Patellamide E [58] cells in vitro 125 µg/mL Lissoclinum patella cultured cyanobacterium Cytotoxicity against Microcyclamide [35] 1.2 µg/mL Microcystis aeruginosa P388 murine leukemia cells sea hare Dolastatin E [76] Cytotoxicity against HeLa-S cells 22–40 µg/mL Dolabella auricularia 3 freshwater Antiparasite activity against Plasmodium cyanobacterium falciparum K1 and Trypanosoma brucei Aerucyclamide A [38] 5.0 and 56.3 µM Microcystis aeruginosa rhodesiense PCC 7806 STIB 900 freshwater Antiparasite activity against Plasmodium cyanobacterium falciparum K1 and Trypanosoma brucei Aerucyclamide B [38] 0.7 and 15.9 µM Microcystis aeruginosa rhodesiense PCC 7806 STIB 900 freshwater Antiparasite activity against Plasmodium cyanobacterium Aerucyclamide C [38] falciparum K1 and Trypanosoma brucei 2.3 and 9.2 µM Microcystis aeruginosa rhodesiense STIB 900 PCC 7806 freshwater Antiparasite activity against Plasmodium cyanobacterium Aerucyclamide D [38] falciparum K1 and Trypanosoma brucei 6.3 and 50.1 µM Microcystis aeruginosa rhodesiense STIB 900 PCC 7806 Mar. Drugs 2020, 18, 329 29 of 43

Table 2. Cont.

Bioactivity TBPs Resource Susceptibilty MICa Value freshwater Grazer toxicity Aerucyclamide A, B and cyanobacterium 30.5, 33.8, and 70.5 against the freshwater crustacean C[37,38] Microcystis aeruginosa µM Thamnocephalus platyurus PCC 7806 freshwater Aerucyclamide B and C cyanobacterium Cytotoxic activity against Rat 120 and 106 µM [38] Microcystis aeruginosa Myoblast L6 cells PCC 7806 marine-derived bacterium Cytotoxicity against A549 human lung Urukthapelstatin A [78] Mechercharimyces 12 nM cancer cells asporophorigenens YM11-542 marine-derived Cytotoxicity against A549 human lung 4.0 10-8 M and 4.6 Mechercharmycin A [79] bacterium × × cancer cells and Jurkat cells 10-8 M Thermoactinomyces sp. Cytotoxic activity against L1210, Ulithiacyclamide marine tunicate 0.35, 0.04, 0.10, and MRC5CV1, T24, and CEM cell lines [56,117] Lissoclinum patella 0.01 µg/mL (continuous exposure) marine tunicate Cytotoxic activity against L1210 murine Ulicyclamide [117] 7.2 µg/mL Lissoclinum patella leukemia cells marine tunicate Cytotoxic activity against L1210 murine Patellamide A [117] 3.9 and 0.028 µg/mL Lissoclinum patella leukemia and human ALL cell line (CEM) marine tunicate Cytotoxic activity against L1210 murine Patellamide B, C [117] 2.0 and 3.2 µg/mL Lissoclinum patella leukemia cells Antiparasitic activity against Plasmodium marine falciparum, Trypanasoma cruzi 8.2 and 14.6 µM Venturamide A [34] cyanobacterium Cytotoxicity against mammalian Vero cells 86 and 13.1 µM Oscillatoria sp. and MCF-7 cancer cells marine Antiparasitic activity against Plasmodium 5.2 and 15.8 µM Venturamide B [34] cyanobacterium falciparum, Trypanasoma cruzi 56 µM Oscillatoria sp. Cytotoxicity against mammalian Vero cells aplousobranch Bistratamides A and B Cytotoxicity against MRC5CV1 ﬁbroblasts ascidian 50 and 100 µg/mL [60] and T24 bladder carcinoma cells Lissoclinum bistratum marine ascidian Cytotoxicity against breast, colon, lung, and Bistratamide M [61] 18, 16, 9.1, and 9.8 µM Lissoclinum bistratum pancreas cell lines freshwater cyanobacterium Antimalarial activity against Plasmodium Balgacyclamide A [33] 9 and 59 µM Microcystis aeruguinosa falciparum K1 EAWAG 251 freshwater Antiparasitic activity against Trypanosoma cyanobacterium Balgacyclamide B [33] brucei 8.2 and 51 µM Microcystis aeruguinosa rhodesiense STIB 900 EAWAG 251 a MIC—minimum inhibitory concentration, b CNS—central nervous system, c KB—ubiquitous KERATIN-forming d tumor cell subline, ED100—eﬀective dose for 100% inhibition.

7. Mechanism of Action Heterocyclic thiazole-based peptides act by a variety of mechanisms including inhibiting microtubule assembly/mitosis, arresting nuclear division, inducing tumor cell apoptosis, causing microtubule depolymerization, inhibiting the protein secretory pathway through preventing cotranslational translocation, inducing G1 cell cycle arrest and an apoptotic cascade, inhibiting the phosphorylation of ERK and Akt, disrupting the cellular actin microfilament network, overproducing 1,3-β-D-glucan, activating the caspase-3 protein expression and decrease in B-cell lymphoma 2 (Bcl-2) levels, inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) luciferase and nitrite production, etc. Dolastatin 10 (20) is a pentapeptide with potential antineoplastic activity, derived from marine mollusk Dolabella auricularia. Its mechanism of action involves the inhibition of tubulin polymerization, tubulin-dependent guanosine triphosphate hydrolysis, and nucleotide exchange, and it is a potent noncompetitive inhibitor of vincristine binding to tubulin. Binding to tubulin, dolastatin 10 (20) Mar. Drugs 2020, 18, 329 30 of 43 inhibits microtubule assembly, resulting in the formation of tubulin aggregates and inhibition of mitosis. This thiazole-containing linear peptide also induces tumor cell apoptosis through a mechanism involving bcl-2, an oncoprotein that is overexpressed in some cancers. Microtubule inhibitors from several chemical classes can block the growth and development of malarial parasites, reflecting the importance of microtubules in various essential parasite functions. Dolastatin 10 (20) was a more potent inhibitor of P. falciparum than any other microtubule inhibitor like dolastatin 15. Dolastatin 10 (20) caused arrested nuclear division and apparent disassembly of mitotic microtubular structures in the parasite, indicating that compounds binding in the “Vinca domain” of tubulin can be highly potent antimalarial agents [185]. Symplostatin 1 (21), an analog of dolastatin 10 (20), is a potent antimitotic with antiproliferative effects that act by causing microtubule depolymerization, formation of abnormal mitotic spindles that lead to mitotic arrest, and initiation of apoptosis involving the phosphorylation of the anti-apoptotic protein Bcl-2. Symplostatin 1 (21) inhibited the polymerization of tubulin in vitro, consistent with its mechanism of action in cells and suggesting that tubulin may be its intracellular target. Additionally, symplostatin 1 (21) was found to inhibit the proliferation and migration of endothelial cells, suggesting that it may have antiangiogenic activity [186]. Largazole is a cyclic peptide with thiazole/thiazoline residues, including a number of unusual structural features, including a 3-hydroxy-7-mercaptohept-4-enoic acid unit and a 16-membered macrocyclic cyclodepsipeptide skeleton. Largazole showed potent and highly selective inhibitory activities against class I HDACs (histone deacetylases) and displayed superior anticancer properties. Largazole was found to strongly stimulate histone hyperacetylation in the tumor, showed efficacy in inhibiting tumor growth and induced apoptosis in the tumor. This effect is likely mediated by modulation of levels of cell cycle regulators, by antagonism of the AKT pathway through IRS-1 downregulation, and by reduction of epidermal growth factor receptor levels [187]. Lyngbyabellins are hectochlorin-related peptides with thiazole moieties that are associated with actin polymerization activity. These lipopeptides were found to induce perceptible thickening of the cytoskeletal elements with a relatable increase in binucleated cells. Lyngbyabellin A was found to disrupt the cellular actin microfilament network in A10 and, accordingly, disrupted cytokinesis in colon carcinoma cells, causing the formation of apoptotic bodies. Lyngbyabellin E exhibited actin polymerization ability and was found to completely block the cellular microfilaments, forming binucleated cells [188]. Scleritodermin A (10) is a cytotoxic cyclic peptide with an unusual N-sulfated side chain and a novel conjugated thiazole moiety as well as an α-ketoamide group. Scleritodermin A (10) has significant in vitro cytotoxicity against a panel of human tumor cells lines, and this depsipeptide acts through inhibition of tubulin polymerization and the resulting disruption of microtubules, which is the target of a number of clinically useful natural product anticancer drugs [64]. Theonellamides are sponge-derived antifungal and cytotoxic bicyclic dodecapeptides with a histidine-alanine bridge. Specific binding of these peptides to 3β-hydroxysterols resulted in overproduction of 1,3-β-D-glucan and membrane damage in yeasts. The inclusion of cholesterol or ergosterol in phosphatidylcholine membranes significantly enhanced the membrane affinity of theonellamide A because of its direct interaction with 3β-hydroxyl groups of sterols. Membrane action of theonellamide A proceeds via binding to the membrane surface through direct interaction with sterols and modification of the local membrane curvature in a concentration-dependent manner, resulting in dramatic membrane morphological changes and membrane disruption. Theonellamides represents a new class of sterol-binding molecules that induce membrane damage and activate Rho1-mediated 1,3-beta-D-glucan synthesis [189]. Phalloidin is a tryptophan containing bicyclic phallotoxin, which functions by binding and stabilizing filamentous actin (F-actin) and effectively prevents the depolymerization of actin fibers. Due to its tight and selective binding to F-actin, derivatives of phalloidin-containing fluorescent tags are used widely in microscopy to visualize F-actin in biomedical research. Though phallotoxins are Mar. Drugs 2020, 18, 329 31 of 43 highly toxic to liver cells, they add little to the toxicity of ingested death cap, as they are not absorbed through the gut [190]. Jaspamide (Jasplakinolide) is a cytotoxic cyclodepsipeptide with bromotryptophan moiety that induces apoptosis in human leukemia cell lines and brain tumor Jurkat T cels by activation of caspase-3 protein expression and decrease in Bcl-2 levels. Apoptosis induced by Jaspamide was associated with caspase-3 activation, decreased Bcl-2 protein expression, and increased Bax levels, suggesting that jaspamide induced a caspase-independent cell death pathway for cytosolic and membrane changes in apoptosis cells and a caspase-dependent cell death pathway for poly (ADP-ribose) polymerase (PARP) protein degradation [191]. Azonazine is a unique peptide with a macrocyclic heterocyclic core of the benzofuro indole ring system with diketopiperazine residue. This hexacyclic dipeptide displayed anti-inflammatory activity and was found to act by inhibiting NF-κB luciferase and nitrite production [192].

8. Issues Associated with Marine Peptides in Drug Development Marine peptides are fascinating therapeutic candidates due to their diverse bioactivities. They demonstrate significant chemical and biological diversity for drug development including minimized drug–drug interaction, less tissue accumulation, and low toxicity. Approximately 40% of existing small molecules and 70% of new candidates under development pipelines suffer from the low solubility problem, which is a major reason for their suboptimal drug delivery as well as failures in their development process. Approaches such as cyclodextrin complexation and solid dispersions have been employed to address this challenge and recommend the better formulation over their existing dosage forms [193–198]. Likewise, peptides, being biomacromolecules, also exhibit various challenges such as limited water solubility, stability aspects, as well as structural and synthesis complexities, limiting their full exploitation in drug development [199,200]. Table3 portrays various issues associated with peptide drug development. Amidst the major challenges, difficulty in optimization of the required peptide length to achieve pharmacologically useful levels for receptor activation accounts for the hindered drug development of marine-based peptides. The optimization depends on variables including the size, accessibility, and fit of ligand-binding surfaces, ligand stability, and receptor residency time. Further, the high proteolytic instability of peptide-based therapeutics can be conquered by alteration of the side chains and amide bonds, which in turn makes the peptide resistant to proteolytic degradation [201]. The challenges of low bioavailability and short half-life can be overpowered by three approaches: (i) modification of the peptide backbone through the introduction of D-amino acids or unnatural amino acids, (ii) alteration of the peptide bonds with reduced amide bonds or β-amino acids, and (iii) attachment of a fatty acid. Approaches (i) and (ii) drive the peptide backbone through introducing cyclization, reduced flexibility, and enzyme digestion. Approach (iii) could lead to more specific binding to the target leading to enhanced half-life and bioavailability with fewer side effects [202]. Intracellular delivery of peptides has been a subject of interest due to their membrane-binding ability to exert action on the cell surface. Also, involving the protein transduction domain allows intracellular peptide delivery. Although the liposomal and nanoparticle drug delivery takes advantage of fusing the peptides for intracellular drug delivery, they also face the problem of low encapsulation efficiency [202]. During the process development of peptide synthesis, it is difficult to identify the critical process parameters to achieve expected purity and yield. In addition, the peptide synthesis process also depends on the specifications or requirements and targeted volumes. However, the establishment of acceptable standards and proven ranges may be lacking, which in turn accelerates their manufacturing costs during drug development. Mar. Drugs 2020, 18, 329 32 of 43

Table 3. Issues associated with marine peptide drug development.

Sr. No. Associated Issue 1. Low bioavailability and short half-life due to instability of peptides in the body 2. Formulation challenges and synthesis challenges including aggregation and solubility problems 3. Diﬃculty optimizing peptide length to pharmacologically useful levels for receptor activation 4. Expensive synthesis and manufacturing cost 5. Diﬃculty in delivering expected purities and yields

9. Peptide Market and Clinical Trials As a class of drugs, peptides are increasingly important in medicine. The Food and Drug Administration (FDA) has seen a rapid increase in the number of new drug applications submitted for peptide drug products. The availability of generic versions of these products will be critical to increasing public access to these important medications. However, ensuring the quality and equivalence between generic and brand-name peptide drug products raises a number of challenges, and those challenges differ according to the type of peptide drug. For peptide drug products with a specifically defined sequence of amino acids, the challenge has been with impurities that may be inadvertently introduced during the production process that may affect a proposed generic drug’s safety profile. Peptide-related impurities can be especially difficult to detect, analyze, and control because they usually have similar sequences to the drug itself. As per the current calculations, the market for peptide and protein drugs is estimated around 10% of the entire pharmaceutical market and will make up an even larger proportion of the market in the future. Since the early 1980s, more than 200 therapeutic proteins and peptides are approved for clinical use by the US-FDA [203]. Promising preclinical data led to clinical evaluation of a thiazole-containing linear pentapeptide, dolastatin 10 (20), isolated from sea hare as well as cyanobacterium. The potent antimitotic compound, dolastatin 10 (20), was evaluated in many phase I and phase II clinical trials for solid tumor, including a multi-institutional phase II clinical trial for soft tissue sarcoma treatment [204]. Dolastatin 10 (20) was withdrawn from clinical trials due to adverse effects such as peripheral neurophathy in cancer patients. Dolastatin 10 (20) was not found to be successful in human clinical trials, but it acted as a valuable source for a number of related compounds with clinical significance like ILX651, LU103793, and soblidotin [205,206]. Chemical modification efforts to reduce toxicity resulted in the synthesis of TZT-1027 (soblidotin or auristatin PE), a microtubule-disrupting compound, which entered a phase II clinical trial in patients with advanced or metastatic soft tissue sarcomas and lung cancer. Soblidotin has not progressed further beyond phase II clinical trials due to the associated hematological toxicities [207]. Although due to poor water solubility dolastatin 15 could not enter clinical trials, the investigations on this linear depsipeptide encouraged the development of its synthetic analogs like synthadotin and cematodin which have entered clinical trials. Preclinical studies confirmed the antitumor potential of the orally active microtubule inhibitor synthadotin against padiatric sarcomas. This depsipeptide has completed three phase II trials for the treatment of hormone refractory prostate cancer and metastatic melanoma that indicated toward the favorable toxicity profiles of synthadotin [208]. Another synthetic analog of dolastatin 15, cemadotin, underwent many phase I and phase II clinical trials against metastatic breast cancer and malignant melanoma. However, clinical trials were discontinued because of inconsiderable cytotoxicity caused by cemadotin in phase II trials and to acute myocardial infarction and neutropenia in phase I clinical trials [209]. Further modifications of soblidotin/auristatin E led to the development of monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF), each of which included a secondary amine at their N-terminus. MMAE and MMAF have been used as warheads to link monoclonal antibodies and are presently in many clinical trials for the treatment of cancer, and eventually various antibody-drug conjugates received FDA approval [210,211]. Mar. Drugs 2020, 18, 329 33 of 43

10. Conclusions and Future Prospects In present times, there is an increased frequency of resistance for conventional drugs. This fact necessitates the focus of drug research to be shifted toward a new era where bioactive compounds are developed with novel mechanisms of action. TBPs with unique structural features claim their candidature to overcome the existing issues. Various bioactive heteroaromatic peptides have been isolated from diﬀerent organisms ranging from marine sponges, mollusks, and tunicates to terrestrial cyanobacteria and other microbes including fungi and bacteria. On this basis, various mimetics of bioactive peptides have been synthesized using solid and solution phase techniques of peptide synthesis. Despite enormous potential, utilization of these bioactive peptides is limited due to their stability and bioavailability issues. This review portrays recent updates and future perspectives of TBPs to attract the attention of researchers and scientists leading the eﬀorts toward their clinical translation from the bench to the bedside.

Author Contributions: R.D., S.D., N.K.F., J.S. and R.M. conceived and designed the structure of the review. R.D., S.D., S.V.C., A.S., H.G. and A.A. conducted literature research and drafted the entire manuscript. S.D., S.M., S.S., S.F. and S.J. edited the manuscript. R.D., S.D., S.K., G.J., A.K., N.K.F., S.F., S.J. and S.K.K. supervised and contributed to the key parts of the text associated with it. All authors have read and agreed to the published version of the manuscript. Funding: This work was partially funded by the Campus Research and Publication Fund Committee of The University of the West Indies, St. Augustine, Trinidad & Tobago. Acknowledgments: The authors wish to thank chief librarians of Faculty of Medical Sciences, The University of the West Indies, St. Augustine, Trinidad & Tobago, WI and University of Puerto Rico, San Juan, PR, USA for providing literature support. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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